Pathophysiology department, General medicine faculty, 2022

Immune pathology

The immune system is vital for survival, because it protects us from infectious pathogens that abound in the
environment. Predictably, immune deficiencies (too little immunity) render individuals easy prey to infections. But
the immune system is itself capable of causing tissue injury and disease, as allergies and autoimmune disorders (too
much immunologic reactivity). First, we review some of the important features of normal immune responses, to
provide a foundation for understanding the abnormalities.

The Normal Immune Response

The classic definition of immunity is protection from infectious pathogens, and the normal immune response
is best understood in this context. The mechanisms of defense against microbes fall into two broad categories (Fig. 1).
Innate immunity (also called natural, or native, immunity) refers to the mechanisms that are ready to react to infections
even before they occur. Innate immunity is the first line of defense. It is mediated by cells and molecules that recognize
products of microbes and dead cells and induce rapid protective host reactions, such as inflammation. Adaptive
immunity (also called acquired, or specific, immunity) consists of mechanisms that are stimulated by (“adapt to”)
microbes and are capable of recognizing microbial and nonmicrobial substances. Adaptive immunity develops later,
after exposure to microbes and other foreign substances, and is even more powerful than innate immunity in combating
infections. By convention, the term immune response usually refers to adaptive immunity. Innate immunity, unlike
adaptive immunity, does not have memory or fine antigen specificity. It is estimated that innate immunity uses about
100 different receptors to recognize 1,000 molecular patterns. In contrast, adaptive immunity uses two types of
receptors (antibodies and T-cell receptors), each with millions of variations, to recognize millions of antigens.

Figure 1. The principal components of innate and adaptive immunity. NK, Natural killer.

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Innate Immunity
The major components of innate immunity are epithelial barriers that block entry of microbes, phagocytic cells
(mainly neutrophils and macrophages), dendritic cells, natural killer (NK) cells, and several plasma proteins, such as
complement system and C-reactive protein.
• Epithelia of the skin and gastrointestinal, respiratory tracts and other mucous membranes provide mechanical barriers
to the entry of microbes from the external environment. Epithelial cells also produce antimicrobial molecules such as
defensins. If microbes do breach epithelial boundaries, other defense mechanisms are called in.
• Monocytes and neutrophils are phagocytes in the blood that can rapidly be recruited to any site of infection;
monocytes that enter the tissues and mature are called macrophages. All tissues contain resident macrophages. These
cells sense the presence of microbes and other offending agents, ingest and destroy them.
• Eosinophils, basophils and mast cells are capable of producing many mediators of inflammation. Eosinophils are only
weakly phagocytic and probably kill parasites mainly by releasing cationic proteins and reactive oxygen metabolites
into the extracellular fluid. Basophils and mast cells possess high-affinity receptors for IgE and thereby become coated
with IgE. These cells are important in allergies such as eczema, hay fever, and asthma, in which allergen binding to
the IgE triggers the cell to secrete inflammatory mediators such as histamine, prostaglandins, and leukotrienes.
• Dendritic cells are a specialized cell population present in epithelia, lymphoid
organs, and most tissues. Dendritic cells are endowed with a rich collection of
receptors that sense microbes and cell damage (TLRs, NLRs). They capture
protein antigens and display peptides for recognition by T lymphocytes (figure
2). In addition to their antigen presenting function, they produce cytokines,
mediators that play critical roles in inflammation and anti-viral defense.
• Natural killer (NK) cells destroy infected and malignant cells. They Figure 2. Dendritic cell-lymphocyte interaction.
recognize their targets in one of two ways. Like many other cells, they
possess Fc receptors that bind IgG. These receptors link natural killer cells to IgG-coated target cells, which they kill
by a process called antibody-dependent cellular
cytotoxicity. The second way of recognition relies on
recognition of MHC class I molecules, which are
usually present on all nucleated cells (shown in the
figure). The killer-inhibitory receptors recognize
MHC class I molecules and prevent cell attack.
Although all nucleated cells normally express MHC
class I molecules, they can sometimes lose this ability.
This loss may occur as a result of either microbial
interference with the expression mechanism — for
example, after herpesvirus infection — or malignant
transformation. Therefore, cells that lack MHC class I
surface molecules are in some way abnormal. This lack
of MHC class I molecules means that there is no
inhibitory signal from the killer-inhibitory receptor,
and the NK cell kills the abnormal target cell by
Figure 3. Activating and inhibitory receptors of natural killers (NK).

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inserting the pore-forming molecule perforin into the membrane of the target cell and then injecting it with cytotoxic
granzymes, which activate caspases and lead to apoptosis (figure 3).
Receptors of innate immune system. Cells that participate in innate immunity are capable of recognizing certain
components that are shared among related microbes. Molecules which are present in microbial cells but not in host
cells are known as pathogen-associated molecular patterns (PAMPs). Bacterial lipopolysaccharides (LPS) of the cell
membranes of gram-negative bacteria, are considered to be the prototypical class of PAMP. Other PAMPs include
bacterial flagellin, lipoteichoic acid from gram-positive bacteria, nucleic acid variants normally associated
with viruses, such as double-stranded RNA (dsRNA) etc.
Leukocytes also recognize molecules released by injured and necrotic cells, which are called damage-associated
molecular patterns (DAMPs). These molecules include uric acid (a product of DNA breakdown), ATP (released from
damaged mitochondria), heat shock proteins, reduced intracellular K+ concentrations (reflecting loss of ions because of
plasma membrane injury), DNA when it is not
sequestered in nuclei, as it should be normally, and
many others. Collectively, the cellular receptors that
recognize above mentioned molecules are called pattern
recognition receptors. Several classes of these receptors
have been identified.
-Toll-like receptors. The best known of the pattern
recognition receptors are the Toll-like receptors (TLRs).
There are 10 TLRs in mammals, and each recognizes a
different set of PAMPs (e.g. LPS4 is specifically
recognized by TLR4). The receptors are expressed on
many cell types, including epithelial cells (through
which microbes enter from the external environment),
dendritic cells, macrophages, and other leukocytes
(which may encounter microbes in various tissues). All
TLRs signal by a common pathway that culminates in
the activation of transcription factor NF-κB, which
stimulates the synthesis and secretion of cytokines and
the expression of adhesion molecules, both of which are
critical for the recruitment and activation of leukocytes.
-NOD-like receptors (NLR) are sensors of cell damage.
They are cytosolic receptors which recognize a wide
variety of substances, including products of necrotic
cells (DAMPs). Several of the NLRs signal via a cytosolic
multiprotein complex called the inflammasome, which
activates an enzyme (caspase-1) that cleaves a precursor
form of the cytokine interleukin-1 to generate the Figure 4. The inflammasome.
biologically active form (figure 4). Caspase-1 cleaves
gasdermin D, to allow its N-terminal fragment to interact
with membrane lipids and to assemble pores that induce pyroptosis, a lytic form of cell death that releases intracellular
contents. These pores contribute to the release of cytokines, which in turn recruit more immune cells to promote
inflammation.
The inflammasome has also been implicated in inflammatory reactions to urate crystals in case of gout, lipids
(in obesity), cholesterol crystals (in atherosclerosis), and even amyloid deposits in the brain (in Alzheimer disease).

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Gain-of-function mutations in NLRs and related proteins, and loss-of-function mutations in regulators of the
inflammasome, result in periodic fever syndromes called autoinflammatory syndromes.

Adaptive Immunity
The adaptive immune system consists of lymphocytes and their products, including antibodies. The
lymphocytes use highly diverse receptors to recognize a vast array of foreign substances. There are two types of adaptive
immunity: humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated (or
cellular) immunity, which is responsible for defense against intracellular microbes. Humoral immunity is mediated by
B (bone marrow–derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins, Ig);
cellular immunity is mediated by T (thymus-derived) lymphocytes. Acquired immune responses involve the
proliferation of antigen-specific B and T cells, which occurs when the surface receptors of these cells bind to antigen.
Specialized antigen-presenting cells (dendritic cells, B lymphocytes and macrophages) display the antigen to T
lymphocytes and collaborate with them in the response to the antigen. B cells secrete antigen-specific antibodies (Table
1) responsible for elimination of extracellular microbes (e.g. IgG acts as opsonin, IgG and IgM activate complement). T
cells help B cells to make antibody and can also eradicate intracellular pathogens by activating macrophages (T helpers,
CD4+ cells, Table 2); T cells can kill virally infected cells (cytotoxic T lymphocytes, T killers, CD8+ cells). Innate and

Figure 5. The principal classes of lymphocytes and their functions.

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acquired responses usually work together to eliminate pathogens. A population of T cells called regulatory T cells
functions to prevent immune reactions against self-antigens (figure 5).
Lymphocytes develop from stem cells in the fetal liver and in bone marrow. B cells reach maturity within the
bone marrow, but T cells must travel to the thymus to complete their development. Bone marrow and thymus are
referred as central lymphoid organs. The initial stages of lymphocyte development do not require the presence of an
antigen. Adaptive immune responses are generated in the lymph nodes, spleen, and mucosa-associated lymphoid tissue
(tonsils, adenoids, and Peyer's patches) after encounter with an antigen. These are referred to as the peripheral
lymphoid tissues.

Table 1. Immunoglobulins and their functions

IgG Most common antibody in the blood. produced in both primary and secondary immune responses, acts as
opsonin, activates complement. Crosses placenta, creates passive immunity in newborn
IgM Produced first in primary immune response, pentameric, activates complement. Present also as a
membrane-bound receptor of B cells
IgA May be dimeric and monomeric. Is secreted as sIgA (secretory IgA) from mucosal epithelia and neutralizes
microbes in the lumens of the respiratory, gastrointestinal tracts and other mucosal tissue surfaces.
IgE Binds to mast cells in skin and mucous membranes, when linked to allergen, causes release of histamine
and other chemicals, resulting in inflammation.
IgD Membrane-bound receptor of B cells

Table 2. Main types of T helpers and their function

T helper 1 (Th1) enhances cellular immune response, activates T killers antiviral, antimycobacterial,
antineoplastic defense
T follicular helper stimulate somatic hypermutation, isotype switching, and the defense against extracellular
(Tfh) generation of memory B cells and long-lived plasma cells. microorganisms
T helper 2 (Th2) switches antibodies production to IgE anti-helminthic defense
T helper 17 (Th17) produces Il-17 and stimulates neutrophils and inflammation antibacterial, antifungal defense

Lymphocytes are capable of producing millions of different antibody variable regions (B cells) and a similar
number of T-cell–receptor variable regions. Remarkably, the vast diversity of the immune repertoire originates from
fewer than 400 genes by unique recombination processes that cut, splice, and modify variable-region genes. Each B
and T cell is programmed to express only one type of antigen recognizing receptor. There are no more than a few
thousand lymphocytes specific for each antigen. Clones of lymphocytes are selected to participate in an immune
response if they bear a receptor that can bind the relevant antigen, a process called clonal selection. The antigen-
selected cells proliferate, leading to a rapid increase in the number of B or T cells that can recognize the antigen. The
proliferation of naive lymphocytes during the first encounter with an antigen, the primary immune response, generates
both effector T and B cells (cytotoxic and helper T cells and antibody-secreting plasma cells) and memory T and B cells.
The memory cells enable a quantitatively and qualitatively superior secondary immune response to be mounted after
a subsequent encounter with the same antigen. Because memory cells are increased in number relative to naive cells
and because memory cells are also more readily triggered, the secondary response is more rapid than the primary
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immune response. It produces a larger number of lymphocytes and, in the case of B cells, induces greater levels of
antibody that has a greater affinity for the antigen than the antibody of the primary response.
Major Histocompatibility Complex (MHC) molecules
Unlike membrane-bound antibody molecule (IgM or IgD), which acts as the antigen receptor on B cells and
recognizes antigen in its native state, the T-cell receptor recognizes short peptides that result from the intracellular
processing of protein antigens, which are presented to the T cell by MHC molecules on the surface of antigen presenting
cells. MHC molecules were discovered as molecules that evoke rejection of transplanted organs, and their name derives
from their role in determining tissue compatibility between individuals. In humans the MHC molecules are also called
human leukocyte antigens (HLA) because they were initially detected on leukocytes. The MHC system is highly
polymorphic, meaning that there are many alleles of MHC genes (in the thousands) in humans and each individual’s
MHC alleles differ from those inherited by other individuals in the population (except identical twins). This constitutes
a formidable barrier in organ transplantation.
Class I MHC molecules are expressed on all nucleated cells and platelets. Class I MHC molecules display peptides
that are derived from proteins, such as viral and tumor antigens, that are located in the cytoplasm and usually produced
in the cell, and class I–associated peptides are recognized by CD8+ T lymphocytes. In this interaction, the T cell
receptor (TCR) recognizes the MHC -peptide complex, and the CD8 molecule, acting as a coreceptor, binds to the MHC
class I. Because one of the important functions of CD8+ CTLs is to eliminate viruses, which may infect any nucleated
cell, and tumors, which may arise from any nucleated cell, it makes good sense that all nucleated cells express class I
MHC molecules and can be surveyed by CD8+ T cells. Cells lacking MHC I molecules are killed by NK cells.
Class II MHC molecules present antigens that are
internalized into vesicles, and are typically derived from
extracellular microbes. The MHC class II has a binding
site for CD4, and therefore, the class II-antigen complex
is recognized by CD4+ T helper cells. In this interaction,
the CD4 molecule acts as the coreceptor (figure 6). In
contrast to class I molecules, class II MHC molecules are
mainly expressed on the immune system cells (dendritic
cells, B lymphocytes and macrophages) that present
ingested antigens and respond to T-cell help.
So, MHC molecules ensure that the correct
immune response is mounted against different
microbes— CTL mediated killing of cells harboring
cytoplasmic microbes, and T helper–mediated antibody
and macrophage activation to combat extracellular
microbes. Figure 6. The T-cell receptor (TCR) complex and other
molecules involved in T-cell activation. The TCR
heterodimer, consisting of an α and a β chain, recognizes
antigen (in the form of peptide-MHC complexes expressed on
antigen-presenting cells, or APCs), and the linked CD3
complex and ζ chains initiate activating signals. CD4 and
CD28 are also involved in T-cell activation.

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Immunodeficiency Syndromes

Immunodeficiencies can be divided into primary (or congenital) immunodeficiency disorders, which are
genetically determined, and secondary (or acquired) immunodeficiencies. Immunodeficiencies are manifested
clinically by increased infections, which may be newly acquired or reactivation of latent infections.
The primary immunodeficiency syndromes
Primary immunodeficiency diseases are genetically determined and affect the defense mechanisms of innate
immunity or the humoral and/or cellular arms of adaptive immunity (mediated by B and T lymphocytes, respectively).
Although these disorders were once thought to be quite rare, some form of mild genetic immune deficiency is, in fact,
present in many individuals. Most primary immunodeficiencies are detected in infancy.
Defects in Innate Immunity typically affect phagocytes, NK cells or the complement system.
• Inherited defects in leukocyte adhesion. These disorders are due to defects in integrins and ligands of selectins.
• Inherited defects in phagolysosome function. One such disorder is Chédiak-Higashi syndrome, an autosomal recessive
condition characterized by defective fusion of phagosomes and lysosomes.
• Inherited defects in microbicidal activity - impairments of “oxidative burst” and inability to generate reactive oxygen
species. Examples are NADPH-oxidase and myeloperoxidase deficiencies.
Defects in Adaptive Immunity are often subclassified on the basis of the primary component involved (B cells or T cells
or both). These immunodeficiencies result from abnormalities in lymphocyte maturation or activation (figure 7).

Figure 7. Defects in adaptive immunity. Shown are

the principal pathways of lymphocyte development
and the blocks in these pathways in selected
diseases. CD40L, CD40 ligand; CVID, common
variable immunodeficiency; SCID, severe
combined immunodeficiency.

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Examples of B cell defects are X-Linked agammaglobulinemia (Bruton's agammaglobulinemia), common variable
immunodeficiency, IgA immunodeficiency and hyper-IgM syndrome, which are characterized by Ig deficiency and
recurrent bacterial infections. T cell defects (e.g. DiGeorge syndrome) are characterized by high risk of viral and fungal
infections. In case of combined defects both T and B cell defects are present (example is severe combined
immunodeficiency). However, these distinctions are not clear-cut; for instance, T-cell defects almost always lead to
impaired antibody synthesis, and hence isolated deficiencies of T cells are often indistinguishable clinically from
combined deficiencies of T and B cells.
B cell defects. X-Linked Agammaglobulinemia (Bruton's Agammaglobulinemia) is caused by mutations in a cytoplasmic
tyrosine kinase, called Bruton tyrosine kinase, which leads to failure of B-cell precursors (pro-B cells and pre-B cells)
to develop into mature B cells. B cells are absent or markedly decreased in the circulation, and the serum levels of all
classes of immunoglobulins are depressed, germinal centers of lymph nodes, Peyer's patches, the appendix, and tonsils
are underdeveloped, plasma cells are absent throughout the body. Mainly bacterial infections are common in these
patients (acute and chronic pharyngitis, bronchitis, pneumonia). The treatment of X-linked agammaglobulinemia is
replacement therapy with immunoglobulins.
IgA Immunodeficiency. The levels of serum and secretory IgA (sIgA) are very low in these patients. The maturation of
naïve B-cells to IgA-producing plasma cells is impaired. Because IgA is the major antibody in external secretions,
mucosal defenses are weakened, and infections occur in the respiratory, gastrointestinal, and urogenital tracts.
Hyper-IgM syndrome. In this disorder, affected patients have IgM antibodies but are deficient in IgG, IgA, and IgE
antibodies. Normally, antigen-activated CD4+ helper T cells activate CD40 on B cells. This interaction triggers Ig class
switching and affinity maturation in B cells. In hyper-IgM syndrome mature B cells are present, but they are incapable
of Ig class switching and affinity maturation, because of a defect in CD4+ helper T cells (mutations in the gene encoding
CD40L) or an intrinsic B-cell defect (mutations involving either CD40 or activation-induced cytidine deaminase, a
DNA-editing enzyme expressed in B cells that is required for Ig class switching and affinity maturation). Clinically,
patients present with recurrent pyogenic infections, because the level of opsonizing IgG antibodies is low. Occasionally,
the IgM antibodies react with blood cells, giving rise to autoimmune hemolytic anemia, thrombocytopenia, and
neutropenia.
Common variable immunodeficiency is a heterogeneous group of disorders in which the common feature is
hypogammaglobulinemia, generally affecting all the antibody classes but sometimes only IgG. Both intrinsic B-cell
defects and abnormalities in helper T cell–mediated activation of B cells may account for the antibody deficiency. The
diagnosis of common variable immunodeficiency is based on exclusion of other well-defied causes of decreased
antibody production.
T cell defects. DiGeorge Syndrome (Thymic Hypoplasia) is a T-cell deficiency that results from failure of development
of the third and fourth pharyngeal pouches. The latter give rise to the thymus, the parathyroids and C cells of the
thyroid. It results from a deletion that maps to chromosome 22q11. Thus, individuals with this syndrome have a
variable loss of T cell–mediated immunity (resulting from hypoplasia or lack of the thymus) and poor defense against
certain fungal and viral infections. The T-cell zones of lymphoid organs—paracortical areas of the lymph nodes and
the periarteriolar sheaths of the spleen—are depleted. Patients may have hypocalcemia leading to tetany because of
lack of the parathyroids, and congenital defects of the heart and great vessels. In addition, the appearance of the mouth,
ears, and facies may be abnormal. Ig levels may be normal or reduced, depending on the severity of the T-cell
deficiency.

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Combined defects. Severe combined immunodeficiency (SCID) represents a complex of genetically distinct syndromes
(often X-linked and autosomal recessive), all having in common defects in both humoral and cell-mediated immune
responses. Persons with SCID are extremely susceptible to recurrent, severe infections by a wide range of bacterial,
fungal, viral pathogens. -X-linked SCID is the most common form, accounting for 50% to 60% of cases. The genetic
defect in the X-linked form is a mutation in the common γ-chain subunit of cytokine receptors. This transmembrane
protein is a signal-transducing component of the receptors for different cytokines which are required for the survival
and proliferation of lymphoid progenitors, particularly T-cell precursors. T-cell numbers are greatly reduced, and
although B cells may be normal in number, antibody synthesis is impaired because of lack of T-cell help.
-Autosomal Recessive SCID. The remaining forms of SCID are autosomal recessive disorders. The most common cause
of autosomal recessive SCID is a deficiency of the enzyme adenosine deaminase (ADA). It has been proposed that
deficiency of the enzyme leads to accumulation of deoxyadenosine and its derivatives (e.g.,
deoxy-ATP), which are toxic to rapidly dividing immature lymphocytes, especially those of the T-cell lineage. Hence
there may be a greater reduction in the number of T lymphocytes than of B lymphocytes.
In both diseases, thymus and other lymphoid tissues are hypoplastic, with marked depletion of T-cell areas and in some
cases both T-cell and B-cell zones.
Secondary (acquired) immune deficiencies
Secondary (acquired) immune deficiencies may be encountered in individuals with cancer, diabetes and other
metabolic diseases, malnutrition, chronic infection, severe stress and in persons receiving chemotherapy or radiation
therapy for cancer, or immunosuppressive drugs (e.g. glucocorticoids) to prevent graft rejection or to treat autoimmune
diseases. The secondary immune deficiencies are more common than the disorders of primary genetic origin. Some of
these secondary immunodeficiency states can be caused by defective lymphocyte maturation (when the bone marrow
is damaged by radiation or chemotherapy or involved by tumors, such as leukemias and metastatic cancers), inadequate
Ig synthesis (as in malnutrition), decreased phagocytosis of microbes (in case of splenectomy) or lymphocyte depletion
(from drugs or severe infections). HIV infection leads to depletion of CD4+ T helper cells. Acquired immunodeficiency
syndrome (AIDS), resulting from infection by HIV, is the best-known secondary immunodeficiency largely because of
its prevalence and its high mortality rate if not treated. The typical patient with AIDS presents with fever, weight loss,
diarrhea, generalized lymphadenopathy, multiple opportunistic infections (fungi Pneumocystis jiroveci and Candida,
viruses cytomegalovirus and herpes simplex virus, atypical and typical mycobacteria, protozoa Toxoplasma gondii and
many others), neurologic disease, and, in many cases, secondary neoplasms. However, the most common
immunodeficiency worldwide results from severe malnutrition. Recent progress has been made in the influence of
vitamin D deficiency in causing failure of immune activation.

Hypersensitivity reactions

Injurious immune reactions, called hypersensitivity, are the basis of the pathology associated with immunologic
diseases. This term arose from the idea that individuals who have been previously exposed to an antigen manifest
detectable reaction to that antigen and are therefore said to be sensitized. Hypersensitivity implies an excessive or
harmful reaction to antigen. There are several important general features of hypersensitivity disorders.
• Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or
endogenous self-antigens. Exogenous antigens include those in dust, pollens, foods, drugs, microbes, and various
chemicals. The immune responses against such exogenous antigens may take a variety of forms, ranging from annoying
but trivial discomforts, such as itching of the skin, to potentially fatal diseases, such as bronchial asthma and
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anaphylaxis. Some of the most common reactions to environmental antigens cause the group of diseases known as
allergy. Immune responses against self, or autologous, antigens, result in autoimmune diseases.
• The mechanisms of tissue injury in hypersensitivity reactions are the same as the effector mechanisms of defense
against infectious pathogens. The problem in hypersensitivity is that these reactions are poorly controlled, excessive,
or misdirected (e.g., against normally harmless environmental and self-antigens).
•The development of hypersensitivity diseases (both allergic and autoimmune) is often associated with the inheritance
of particular susceptibility genes and have genetic predisposition.
Classification of Hypersensitivity Diseases. Hypersensitivity diseases can be classified on the basis of the
immunologic mechanism that mediates the disease. This classification is of value in distinguishing the manner in which
the immune response causes tissue injury and disease, and the accompanying pathologic and clinical manifestations.
The main types of hypersensitivity reactions are the following (Table 3):
• In immediate hypersensitivity (type I hypersensitivity), the injury is caused by T helper 2 cells, IgE antibodies, and
mast cells and other leukocytes. Mast cells release mediators that act on vessels and smooth muscle and
proinflammatory cytokines that recruit inflammatory cells.
• In antibody-mediated disorders (type II hypersensitivity), secreted IgG and IgM antibodies injure cells by promoting
their phagocytosis or lysis and injure tissues by inducing inflammation. Antibodies may also interfere with cellular
functions and cause disease without tissue injury.
• In immune complex–mediated disorders (type III hypersensitivity), IgG and IgM antibodies bind antigens usually in
the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation. The leukocytes that
are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and free radicals.
• In cell-mediated immune disorders (type IV hypersensitivity), sensitized T lymphocytes (TH1, TH17 cells and
cytotoxic T-cells), recruited neutrophils and monocytes are the cause of the tissue injury.
Table 3. Mechanisms of hypersensitivity reactions.

Type Immune Mechanisms Histopathologic Lesions Prototypical Disorders

Immediate Production of IgE antibody → immediate Vascular dilation, edema, Anaphylaxis; allergies;
(type I) release of vasoactive amines and other smooth muscle contraction, bronchial asthma (atopic
hypersensitivity mediators from mast cells; later mucus production, tissue forms)
recruitment of inflammatory cells injury, inflammation
Antibody- Production of IgG, IgM → binds to Phagocytosis and lysis of cells; Autoimmune hemolytic
mediated antigen on target cell or tissue → inflammation; in some anemia; Goodpasture
(type II) phagocytosis or lysis of target cell by diseases, cell dysfunction syndrome
hypersensitivity activated complement or Fc receptors; without cell lysis
recruitment of leukocytes
Immune Deposition of antigen-antibody Inflammation, necrotizing Inflammation, necrotizing
complex– complexes → complement activation → vasculitis (fibrinoid necrosis) vasculitis (fibrinoid necrosis)
mediated recruitment of leukocytes by complement Systemic lupus
(type III) products and Fc receptors → release of erythematosus; some forms of
hypersensitivity enzymes and other toxic molecules glomerulonephritis; serum
sickness; Arthus reaction
Cell-mediated Activated T lymphocytes → (1) release of Perivascular cellular Contact dermatitis; multiple
(type IV) cytokines, inflammation and macrophage infiltrates; edema; granuloma sclerosis; type 1 diabetes
hypersensitivity activation; (2) T cell–mediated formation; cell destruction
cytotoxicity

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Immediate (Type I) Hypersensitivity
Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring in a previously sensitized
individual that is triggered by the binding of an antigen to IgE antibody on the surface of mast cells. These reactions are
often called allergy, and the antigens that elicit them are allergens. Immediate hypersensitivity may occur as a systemic
disorder or as a local reaction. The systemic reaction most often follows injection of an antigen into a sensitized
individual (e.g., by a bee sting), but can also follow antigen ingestion (e.g., peanut allergens). Sometimes, within
minutes the patient goes into a state of shock, which may be fatal. Local reactions may take the form of localized
cutaneous rash or blisters (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis),
hay fever, bronchial asthma, or allergic gastroenteritis (food allergy). Many local type I hypersensitivity reactions have
two well-defined phases. The immediate reaction is characterized by vasodilation, vascular leakage, and depending on
the location, smooth muscle spasm or glandular secretions. These changes usually become evident within minutes after
exposure to an allergen. Late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may
last for several days. Most immediate hypersensitivity disorders are caused by excessive TH2 responses and these cells
play a central role by stimulating IgE production and promoting inflammation.
Activation of TH2 Cells and Production of IgE Antibody. The first step in the generation of TH2 cells is the
presentation of the antigen to naive CD4+ helper T cells, probably by dendritic cells that capture the antigen (allergen)
from its site of entry. In response to antigen and other stimuli, including cytokines such as IL-4 produced at the local
site, the T cells differentiate into TH2 cells. The newly minted TH2 cells produce IL-4 and IL-5. IL-4 acts on B cells to
stimulate IgE production and promotes the development of additional TH2 cells. IL-5 is involved in the development
and activation of eosinophils, which are important effectors of type I hypersensitivity.
Sensitization and Activation of Mast Cells. Because mast cells are central to the development of immediate
hypersensitivity, we first review some of their salient characteristics. Mast cells are bone marrow–derived cells that
are widely distributed in the tissues. Mast cells have cytoplasmic membrane-bound granules that contain a variety of
biologically active mediators, described later. Mast cells (and their circulating counterpart, basophils) express a high-
affinity receptor, which is specific for the Fc portion of IgE and therefore avidly binds IgE antibodies. Mast cells and
basophils are activated by the cross-linking of high-affinity IgE receptors, when latter bind antigen; in addition, mast
cells may also be triggered by several other stimuli, such as complement components C5a and C3a (called
anaphylatoxins because they elicit reactions that mimic anaphylaxis). IgE-coated mast cells are said to be sensitized,
because they are sensitive to subsequent encounter with the specific antigen. When a mast cell, armed with IgE
antibodies previously produced in response to an antigen, is exposed to the same antigen, the cell is activated, leading
eventually to the release of an arsenal of powerful mediators responsible for the clinical features of immediate
hypersensitivity reactions.
Mast cell activation leads to degranulation, with the discharge of preformed (primary) mediators that are stored
in the granules, and de novo synthesis and release of secondary mediators, including lipid products and cytokines (Fig.
8).
Preformed Mediators. Mediators contained within mast cell granules are the first to be released and can be
divided into three categories:
• Histamine. Histamine causes intense smooth muscle contraction, increased vascular permeability, and increased
mucus secretion by nasal, bronchial, and gastric glands.
• Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate. The proteoglycans serve
to package and store the amines in the granules.

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• Enzymes. These are contained in the granule matrix
and include proteases and hydrolases. The enzymes
cause tissue damage and lead to the generation of
kinins and activated components of complement
(e.g., C3a) by acting on their precursor proteins.
Secondary mediators. Lipid Mediators. The
major lipid mediators are arachidonic acid–derived
products. Reactions in the mast cell membranes lead
to activation of phospholipase A2, an enzyme that
converts membrane phospholipids to arachidonic
acid. This is the compound from which leukotrienes
and prostaglandins are produced by the lipoxygenase
and cyclooxygenase pathways, respectively.
Leukotrienes C4 and D4 are the most potent
vasoactive and spasmogenic agents known. They are
several thousand times more active than histamine in
increasing vascular permeability and causing
bronchial smooth muscle contraction. Leukotriene
B4 is highly chemotactic for neutrophils, eosinophils,
and monocytes.
Cytokines. Mast cells are sources of many
cytokines, including TNF, IL-1, and chemokines,
which promote leukocyte recruitment (typical of the
late-phase reaction); IL-4, which amplifies the TH2
Figure 8. Mast cell mediators.
response.
These mediators are responsible for the
manifestations of immediate hypersensitivity reactions. Some, such as histamine and leukotrienes, are released rapidly
from sensitized mast cells and are responsible for the edema, rash, mucus secretion, and smooth muscle spasm
(bronchospasm). In the late-phase reaction, leukocytes are recruited that amplify and sustain the inflammatory
response without additional exposure to the triggering antigen. Eosinophils are recruited to sites of immediate
hypersensitivity and liberate proteolytic enzymes which damage tissues.
Susceptibility to immediate hypersensitivity reactions is genetically determined. An increased risk to develop
immediate hypersensitivity reactions is called atopy. Atopic individuals tend to have higher serum IgE levels and more
IL-4–producing TH2 cells than does the general population. A positive family history of allergy is found in 50% of
atopic individuals. Environmental factors are also important in the development of allergic diseases. Exposure to
environmental pollutants is an important predisposing factor for allergy. Viral infections of the airways are important
triggers for bronchial asthma, an allergic disease affecting the lungs. Bacterial skin infections are strongly associated
with atopic dermatitis. The incidence of many allergic diseases is increasing in developed countries, and seems to be
related to a decrease in infections during early life. These observations have led to an idea, sometimes called the hygiene
hypothesis, that early childhood and even prenatal exposure to microbial antigens educates the immune system in such
a way that subsequent pathologic responses against common environmental allergens are prevented. Thus, too much
hygiene in childhood may increase allergies later.

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Examples of diseases by type I hypersensitivity.
Local Immediate Hypersensitivity Reactions. About 10% to 20% of the population suffers from allergies
involving localized reactions to common environmental allergens, such as pollen, animal dander, house dust, foods,
and the like. Specific diseases include urticaria, allergic rhinitis (hay fever), bronchial asthma, and food allergies.
Systemic Anaphylaxis. Systemic anaphylaxis is characterized by vascular shock, widespread edema, and
difficulty in breathing. It may occur in sensitized individuals in hospital settings after administration of drugs (e.g., the
antibiotic penicillin), or in the community setting following exposure to food allergens (e.g., peanuts, shellfish) or
insect toxins (e.g., those in bee venom). Extremely small doses of antigen may trigger anaphylaxis, for example, the
tiny amounts used in skin testing for various forms of allergies. Within minutes after exposure, itching, hives, and skin
erythema appear, followed shortly thereafter by a striking contraction of bronchioles. Laryngeal edema results in
hoarseness and further compromises breathing. Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction
follow, and the patient may go into shock and even die within the hour.

Antibody-Mediated (Type II) Hypersensitivity

Antibodies that react with antigens present on cell surfaces cause disease by destroying these cells, triggering
inflammation, or interfering with normal functions. The antibodies may be specific for normal cell or tissue antigens
(autoantibodies) or for exogenous antigens, such as drug or microbial proteins, that bind to a cell surface.
A. Opsonization and Phagocytosis. Phagocytosis is largely responsible for depletion of cells coated with
antibodies. Cells opsonized by IgG antibodies are recognized by phagocyte receptors for Fc portions of IgG. In addition,
when IgM or IgG antibodies are deposited on the surfaces of cells, they may activate the complement system by the
classical pathway. Complement activation generates by-products, mainly C3b, that is also opsonin. The net result is
phagocytosis of the opsonized cells and their destruction (Fig. 9, A). Complement activation on cells also leads to the
formation of the membrane attack complex, which disrupts membrane integrity thereby causing osmotic lysis of the
cells. Antibody-mediated destruction of cells may occur by another process called antibody-dependent cellular
cytotoxicity: cells that are coated with IgG antibody are killed by NK cells without phagocytosis.
Clinically, antibody-mediated cell destruction and phagocytosis occur in the following situations: (1)
transfusion of incompatible blood, (2) hemolytic disease of the newborn, (3) autoimmune hemolytic anemia,
agranulocytosis (destruction of neutrophils), and thrombocytopenia, in which individuals produce antibodies to their
own blood cells, which are then destroyed; and (4) certain drug reactions, in which a drug acts as a “hapten” by
attaching to plasma membrane proteins of red cells and antibodies are produced against the drug-protein complex.
B. Inflammation. When antibodies deposit in fixed tissues, such as basement membranes and extracellular
matrix, the resultant injury is due to inflammation. The deposited antibodies activate complement, including
chemotactic agents (mainly C5a), which direct the migration of polymorphonuclear leukocytes and monocytes, and
anaphylatoxins (C3a and C5a), which increase vascular permeability (Fig. 9, B). The leukocytes are activated by
engagement of their C3b and Fc receptors. This results in the production of the substances that damage tissues, such as
lysosomal enzymes, including proteases capable of digesting tissue components and free radicals.
C. Cellular Dysfunction. In some cases, antibodies directed against cell surface receptors impair or dysregulate
function without causing cell injury or inflammation (Fig. 9, C). For example, in myasthenia gravis, antibodies reactive
with acetylcholine receptors in skeletal muscles block neuromuscular transmission and therefore cause muscle
weakness. The converse (i.e., antibody-mediated stimulation of cell function) is the basis of Graves’ disease. In this

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disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells,
resulting in hyperthyroidism.

Figure 9. Mechanisms of antibody-mediated injury. (A) Opsonization of cells by antibodies and complement components and
ingestion by phagocytes. (B) Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement
breakdown products. (C) Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies to
the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-
stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.

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Immune Complex–Mediated (Type III) Hypersensitivity
.Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition.
The pathologic reaction is usually initiated when antigen
combines with antibody in the circulation, creating immune
complexes that typically deposit in vessel walls. The antigens
that form immune complexes may be exogenous, such as a
foreign protein that is injected or produced by an infectious
microbe, or endogenous, if the individual produces antibody
against self-antigens (autoimmunity). Immune complex–
mediated diseases tend be systemic, but often preferentially
involve the kidney, joints, and small blood vessels, all of
which are common sites of immune complex deposition.
Systemic Immune Complex Disease. Acute serum
sickness is the prototype of a systemic immune complex
disease; in case of administration of large amounts of foreign
serum (e.g., serum from immunized horses used for protection
against diphtheria). The pathogenesis of systemic immune
complex disease can be divided into three phases (Fig. 10).
1. Formation of immune complexes. The introduction of a
protein antigen triggers an immune response that results in
the formation of antibodies, typically about a week after the
injection of the protein. These antibodies are secreted into the
blood, where they react with the antigen still present in the
circulation and form antigen-antibody complexes.
2. Deposition of immune complexes. In the next phase the
circulating antigen-antibody complexes are deposited in
various tissues. Organs where blood is filtered at high pressure
to form other fluids, like urine and synovial fluid (in joints),
are sites where immune complexes become concentrated and
tend to deposit; hence, immune complex disease often affects
glomeruli and joints.
3. Inflammation and tissue injury. Once immune complexes
are deposited in the tissues, they initiate an acute
inflammatory reaction. It is clear that complement-fixing Figure 10. Immune complex disease. The sequential phases
antibodies (i.e., IgG and IgM) and antibodies that bind to in the induction of systemic immune complex–mediated
leukocyte Fc receptors (for IgG) induce the pathologic lesions diseases (type III hypersensitivity).
of immune complex disorders. The mechanisms of
inflammation and injury were discussed above, in the discussion of antibody-mediated (type II) injury. The resultant
inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli,
arthritis if it occurs in the joints, and so on. Clinical features such as fever, joint pains (arthralgias) and proteinuria
(glomerular damage leads to filtration of proteins) appear.

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Local Immune Complex Disease (Arthus Reaction). The Arthus reaction is a localized area of tissue necrosis
resulting from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced
experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating
antibodies against the antigen.
The principal morphologic manifestation of immune complex injury is acute vasculitis, associated with necrosis
of the vessel wall and intense neutrophilic infiltration.

T Cell–Mediated (Type IV) Hypersensitivity

The cell-mediated (IV type) hypersensitivity is caused by inflammation resulting from cytokines produced by
CD4+ T cells and cell killing by CD8+ T cells (Fig. 11). CD4+ T cell–mediated hypersensitivity induced by environmental
and self-antigens is the cause of many chronic inflammatory diseases, including autoimmune diseases. CD8+ cells may
also be involved in some of these autoimmune diseases and may be the dominant effector cells in certain reactions,
especially those that follow viral infections.

Figure 11. Mechanisms of T-cell–mediated (type IV) hypersensitivity reactions. (A) CD4 + Th1 cells (and sometimes
CD8 + T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and
activate phagocytes, leading to tissue injury. CD4 + Th17 cells contribute to inflammation by recruiting neutrophils
(and, to a lesser extent, monocytes). (B) In some diseases, CD8 + cytotoxic T lymphocytes directly kill tissue cells.
APC, Antigen-presenting cell.

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A. CD4+ T Cell–Mediated Inflammation. In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced
by the T cells induce inflammation that may be chronic and destructive. The prototype of T cell–mediated inflammation
is delayed-type hypersensitivity (DTH). In this reaction, an antigen administered into the skin of a previously
immunized individual results in a detectable cutaneous reaction within 24 to 48 hours (hence the term delayed, in
contrast to immediate hypersensitivity). Both TH1 and TH17 cells contribute to organ-specific diseases in which
inflammation is a prominent aspect of the pathology. The inflammatory reactions stimulated by CD4+ T cells can be
divided into sequential stages:
a) Activation of CD4+ T Cells. As described earlier, naïve CD4+ T cells recognize peptides displayed by dendritic cells.
The subsequent differentiation of antigen-stimulated T cells to TH1 or TH17 cells is driven by the cytokines produced
by APCs. Some of the differentiated cells enter the circulation and may remain in the memory pool of T cells for long
periods, sometimes years.
b) Responses of Differentiated Effector T Cells. Upon repeat exposure to an antigen, TH1 cells secrete cytokines, mainly
IFN-γ. IFN-γ-activated macrophages phagocytose and kill microorganisms, secrete TNF, IL-1, and chemokines, which
promote inflammation and they amplify the TH1 response. Thus, activated macrophages serve to eliminate the
offending antigen; if the activation is sustained, continued inflammation and tissue injury result. Activated TH17 cells
secrete IL-17 that recruit neutrophils and monocytes to the reaction, thus promoting inflammation.
The classic example of DTH is the tuberculin reaction, which is produced by the intracutaneous injection of
tuberculin, a protein-containing antigen of the tubercle bacillus. In a previously sensitized individual, reddening and
induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter slowly subside.
Morphologically, delayed-type hypersensitivity is characterized by the accumulation of mononuclear cells, mainly
CD4+ T cells and macrophages, around venules. It
can also be caused by indigestible foreign bodies,
which activate macrophages without eliciting an
adaptive immune response. Contact dermatitis is a
common example of tissue injury resulting from
DTH reactions. It may be evoked by contact with
metals (nickel, mercury, chromium cobalt, gold)
and drugs. It is thought that in these reactions, the
environmental chemical binds to and structurally
modifies some self-proteins and peptides derived
from these modified proteins are recognized by T
cells and elicit the reaction (figure 12). Figure 12. Nickel allergic contact dermatitis.
B. CD8+ T Cell–Mediated Cytotoxicity:
CD8+ cytotoxic T cells (CTLs) kill antigen-expressing target cells. Tissue destruction by CTLs may be an important
component of type 1 diabetes, graft rejection and reactions against viruses. In a virus-infected cell, viral peptides are
displayed by class I MHC molecules and the complex is recognized by CD8+ T lymphocytes. The killing of infected
cells leads to the elimination of the infection, but in some cases, it is responsible for cell damage that accompanies the
infection (e.g., in viral hepatitis). Tumor-associated antigens are also presented on the cell surface, and CTLs are
involved in the host response to transformed cells. Principal mechanism of T cell–mediated killing of targets involves
perforins and granzymes, preformed mediators contained in the lysosome-like granules of CTLs. Perforin facilitates
the release of the granzymes which induce apoptosis of the target cells.

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Autoimmune Diseases
Immune reactions against self-antigens—autoimmunity— are an important cause of certain diseases in
humans. A growing number of diseases have been attributed to autoimmunity.
It is obvious that autoimmunity results from the loss of self-tolerance, and the question arises as to how this
happens. Before we look for answers, we review the mechanisms of immunologic tolerance to self-antigens.

Immunologic Tolerance

Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of

lymphocytes to that antigen. Self-tolerance refers to lack of responsiveness to self-antigens, and it underlies our ability
to live in harmony with our cells and tissues. Because the antigen receptors of lymphocytes are generated by somatic
recombination of genes in a random fashion, lymphocytes with receptors capable of recognizing self-antigens are
generated constantly, and these cells have to be eliminated or inactivated as soon as they recognize self-antigens, to
prevent them from causing harm. The mechanisms of self-tolerance can be classified into two groups: central tolerance
and peripheral tolerance (Fig. 13).

Figure 13. Mechanisms of immunologic tolerance to self-antigens.

Central Tolerance. In this process, immature self-reactive T and B lymphocyte clones that recognize self-
antigens during their maturation in the central lymphoid organs (the thymus for T cells and the bone marrow for B
cells) are killed or rendered harmless. The mechanisms of central tolerance in T and B cells show some similarities and
differences.
• If T lymphocytes express high-affinity receptors for self-antigens, many of the cells die by apoptosis when
encounter the antigens in the thymus. This process, called negative selection, is responsible for eliminating self-reactive

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lymphocytes from the T-cell pool. A wide variety of autologous protein antigens, including antigens thought to be
restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in association with self
MHC molecules and can, therefore, be recognized by potentially self-reactive T cells. In the CD4+ T-cell lineage, some
of the cells that see self-antigens in the thymus do not die but develop into regulatory T cells (discussed later).
• When developing B cells strongly recognize self-antigens in the bone marrow, many of the cells reactivate
the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for
self-antigens. This process is called receptor editing; it is estimated that a quarter to half of all B cells in the body may
have undergone receptor editing during their maturation. If receptor editing does not occur, the self-reactive cells
undergo apoptosis, thus purging potentially dangerous lymphocytes from the mature pool.
Central tolerance, however, is imperfect. Not all self-antigens may be present in the thymus, and hence T cells
bearing receptors for such autoantigens escape into the periphery. There is similar “slippage” in the B-cell system. Self-
reactive lymphocytes that escape negative selection can inflict tissue injury unless they are deleted or muzzled in the
peripheral tissues.
Peripheral Tolerance. Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues;
these are best defined for T cells. These mechanisms include the following:
• Anergy. Lymphocytes that recognize self-antigens may be rendered functionally unresponsive; a phenomenon
called anergy. Activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association
with self MHC molecules on the surface of antigen-presenting cells (APC) and a set of costimulatory signals (“second
signals”) from APCs. These second signals are provided by certain T cell–associated molecules, such
as CD28, that bind to their ligands (the costimulators B7-1 and B7-2) on APCs. If the antigen is presented to T cells
without adequate levels of costimulators, the cells become anergic. When APCs are presenting self-antigens, level of
costimulatory B7 molecules is low and can’t activate CD28 receptor, because another molecule, CTLA-4, binds B7 with
higher affinity and, thus, prevent its binding by CD28. CTLA-4 functions both by scavenging B7 ligands away from
CD28 and by direct negative signaling to T cells. When APCs are presenting foreign antigens, they express high levels
of B7, enough to engage also CD28.
Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self-antigen in
peripheral tissues in the absence of specific helper T cells, the B cells become unable to respond.
• Suppression by regulatory T cells. A population of T cells called CD4+ regulatory T cells functions to prevent
immune reactions against self-antigens. Regulatory T cells develop mainly in the thymus, as a result of recognition of
self-antigens, under the influence of certain cytokines, e.g., IL-2. Both IL-2 and transcriptional factor FOXP3
are required for the development and maintenance of functional CD4 + regulatory T cells. Mutations in FOXP3 result
in severe autoimmune disease called IPEX (an acronym for immune dysregulation, polyendocrinopathy, enteropathy,
X-linked). Mutation of the gene encoding IL-2 or the IL-2 receptor (CD25) also results in a rare multiorgan autoimmune
disease. Recent genome-wide association studies have revealed that polymorphisms in the promoter of the CD25 gene
are associated with different autoimmune diseases, raising the possibility of a regulatory T-cell defect contributing to
these diseases. The mechanisms by which regulatory T cells suppress immune responses are not fully defined, but their
inhibitory activity may be mediated by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which
inhibit lymphocyte activation and effector functions. Regulatory T cells also express high-affinity receptors for
costimulatory molecules on APCs and reduce their availability to activate T cells.
• Deletion by apoptosis. T cells that recognize self-antigens may receive signals that promote their death by
apoptosis (e.g., via FAS-mediated apoptosis).

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• Some antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens
are located do not communicate with the blood and lymph. As a result, self-antigens in these tissues fail to elicit
immune responses and are essentially ignored by the immune system. This is believed to be the case for the testis,
thyroid, eye, and brain, all of which are called immune-privileged sites because it is difficult to induce immune
responses to antigens introduced into these sites. If the antigens of these tissues are released, for example, as a
consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation
and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis.

Mechanisms of Autoimmunity

The immune system normally exists in an equilibrium in which lymphocyte activation, which is required for
defense against pathogens, is balanced by the mechanisms of tolerance, which prevent reactions against self-antigens.
Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the
breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the
activation of self-reactive lymphocytes.
Susceptibility genes include genes encoding MHC (HLA) molecules, which are involved in antigen
presentation, genes encoding cytokines which control the maintenance of regulatory T cells and many others, which
regulate central and peripheral tolerance (e.g., CTLA4, FAS, FASL, and IL2 and its receptor CD25).
Role of Infections. Autoimmune reactions may be triggered by infections. Two mechanisms have been
postulated to explain the link between infections and autoimmunity. First, infections may upregulate the expression
of costimulatory molecules on APCs. If these cells are presenting self-antigens, the result may be a breakdown of anergy
and activation of T cells specific for the self-antigens. Second, some microbes may
express antigens that have the same amino acid sequences as self-antigens. Immune
responses against the microbial antigens may result in the activation of self-reactive
lymphocytes. This phenomenon is called molecular mimicry. A clear example of such
mimicry is rheumatic heart disease, in which antibodies against streptococcal proteins
cross-react with myocardial proteins and cause myocarditis. Additionally, some
viruses, such as EBV and HIV, cause polyclonal B-cell activation, which may result in
production of autoantibodies. Some bacteria (e.g., Staphylococcus aureus and
Streptococcus pyogenes) produce superantigens, causing polyclonal T-cell
proliferation by binding to MHC II molecules, to relatively conserved portions of T-
cell receptor β chains and to co-stimulatory molecule CD28 (Figure 14). In this Figure 14. Mechanisms of action
manner, superantigens may stimulate up to 20% of T lymphocytes; some of these of superantigens.
lymphocytes can be self-reactive.
The tissue injury that is common in infections may release self-antigens and structurally alter these antigens so
that they are able to activate T cells that would not be tolerant to these new, modified antigens. For example,
experimental evidence collected in the past decade suggests that neutrophil extracellular traps (NETs) be important for
the initiation of autoimmune responses in susceptible individuals. Many of the molecules externalized through NET
formation are considered to be key autoantigens in systemic autoimmunity (e.g., myeloperoxidase, double-stranded
DNA, histones). The imbalance between NET formation and degradation might increase the half-life of these molecules
and enhance the exposure of the immune system to modified autoantigens. This autoantigen modification may arise
from critical steps in NET formation which include ROS generation, histone citrullination and chromatin
decondensation, and the proximity of the DNA and other cell molecules to ROS can promote their oxidation.

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Autoimmunity has a strong gender bias, with many of these diseases being more common in women than in
men. The underlying mechanisms are not understood but may involve the effects of hormones and currently
unknown genes on the X chromosome.
Mechanisms of immune-mediated tissue damage. Autoimmune diseases are usually chronic and progressive,
and the type of tissue injury is determined by the nature of the dominant immune response. Some of these diseases are
caused by autoantibodies, leading to type II and type III hypersensitivity reactions (myasthenia gravis, Graves disease,
autoimmune thrombocytopenia, anemia, neutropenia, systemic lupus erythematosus). Some of them are caused by
abnormal and excessive TH1, TH17 and CD8+ CTLs responses (type IV hypersensitivity reactions); examples of these
diseases include psoriasis, multiple sclerosis and type 1 diabetes. In some autoimmune diseases, such as rheumatoid
arthritis, both antibodies and T cell–mediated inflammation may be involved.
The clinical manifestations of autoimmune disorders are extremely varied. On one end are conditions in which
the immune responses are directed against a single organ or tissue, resulting in organ-specific disease, and on the other
end are diseases in which the autoimmune reactions are against widespread antigens, resulting in systemic or
generalized disease. The systemic diseases tend to involve blood vessels and connective tissues, and therefore, they are
often called collagen vascular diseases or connective tissue diseases.
Examples of organ-specific autoimmune diseases are: 1) type 1 diabetes mellitus, in which the autoreactive T
cells and antibodies attack β cells of the pancreatic islets; 2) multiple sclerosis, in which autoreactive T cells react against
central nervous system myelin; 3) myasthenia gravis and Graves disease, in which antireceptor antibodies disturb the
normal function of receptors; 4) autoimmune thrombocytopenia, anemia, neutropenia due to antibody-mediated cell
destruction and phagocytosis.
Examples of systemic autoimmune diseases are systemic lupus erythematosus (SLE), rheumatoid arthritis,
Sjogren syndrome and scleroderma (systemic sclerosis). In SLE a diversity of antibodies directed against DNA, platelets,
red cells, and protein-phospholipid complexes result in widespread lesions throughout the body. Rheumatoid arthritis
is an autoimmune disorder that attacks the joints and extraarticular tissues, and anti-citrullinated peptide antibodies
(ACPAs) are diagnostic markers.

Autoinflammatory diseases

Autoinflammatory diseases are caused by genetic mutations in molecules that are involved in the innate
immune response. In contrast to autoinflammatory diseases, autoimmune diseases are caused by the dysfunction of
adaptive immune system. Familial Mediterranean Fever (FMF) is the most common of all the known autoinflammatory
diseases. FMF is an is autosomal recessive disease usually affecting people of Mediterranean origin, including Armenian,
Jewish, Arab. FMF is related to mutations of a gene, which encodes pyrin. Defect in pyrin molecule leads to
inappropriate activation of pyrin regulated inflammasome, with consequent release of proinflammatory cytokines,
resulting in recurrent episodes of fever and painful serositis, e.g., inflammation in the abdominal cavity (peritonitis)
and in the pleural cavity (pleuritis). Repeated overproduction of acute phase protein serum amyloid A (SAA) leads to
amyloid deposition in different organs, commonly kidneys, which may progress to end-stage renal disease if left
untreated. A potent anti-inflammatory drug colchicine is a widely accepted life-long treatment of FMF.

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Rejection of Tissue Transplants (Allografts)

A major barrier to transplantation is the process of rejection, in which the recipient’s immune system recognizes the
graft as being foreign and attacks it. Rejection is a process in which T lymphocytes and antibodies produced against
graft antigens react against and destroy tissue grafts. The major antigenic differences between a donor and recipient
that result in rejection of transplants are differences in MHC alleles. Because MHC genes are highly polymorphic, there
are always some differences between individuals (except, of course, identical twins). The rejection response is initiated
mainly by host T cells that recognize the foreign MHC antigens of the graft, either directly (on APCs in the graft) or
indirectly (after uptake and presentation by host APCs). Both T cell–mediated reactions (via mechanisms of type IV
hypersensitivity) and antibody-mediated reactions (mainly via mechanisms of type II hypersensitivity) are triggered.
They lead to graft injury and organ failure. There are three types of graft rejection - hyperacute, acute and
chronic. Hyperacute rejection occurs within minutes of the transplantation. Rejection is due to preformed
antibodies that recognize graft antigens. The patient’s serum must be tested for antibodies that bind to a
biopsy of the graft tissue before transplantation. The kidney would show fibrinoid necrosis of the small
vessels and thromboses. Acute rejection is primarily cell mediated, although antibodies can also cause damage
to graft tissue. A biopsy reveals T-cell and macrophage infiltrates as well as blood vessel and parenchymal
damage. Chronic rejection is characterized by vascular damage. Damage to graft blood vessels can be due to
antibody binding, complement activation, T-cell activation, and cytokines. the result is intimal proliferation,
causing narrowing of the vessel lumen and tissue ischemia. examination of the graft shows a small, scarred
kidney.

Table 4. Types of graft rejection.

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Methods of Increasing Graft Survival

The value of MHC matching between donor and recipient varies in different solid-organ transplants. In kidney
transplants, there is substantial benefit of MHC matching. However, MHC matching is usually not even done for
transplants of liver, heart, and lungs, because other considerations, such as anatomic compatibility, severity of the
underlying illness, and the need to minimize the time of organ storage, override the potential benefits of MHC
matching. Except for identical twins, who obviously express the same histocompatibility antigens, immunosuppressive
therapy is a practical necessity in all other donor-recipient combinations. Immunosuppressive drugs in current use
include glucocorticoids and other drugs. Other, more recent strategies, being tested for reducing antigraft immune
responses include injecting regulatory T cells, and blocking the costimulatory signals that are required for T
lymphocyte activation.
Although immunosuppression prolongs graft survival, it carries its own risks. The price paid in the form of
increased susceptibility to opportunistic infections is not small. One of the most frequent infectious complications is
reactivation of latent viral infections (Epstein-Barr virus, cytomegalovirus, human papilloma virus etc.).

Transplantation of Hematopoietic Stem Cells

Use of hematopoietic stem cell (HSC) transplants for hematologic malignancies, bone marrow failure
syndromes (such as aplastic anemia), and disorders caused by inherited HSC defects (such as sickle cell anemia,
thalassemia, and immunodeficiency states) is increasing in number each year. Historically, HSCs were obtained from
the bone marrow, but now they usually are harvested from peripheral blood after they are mobilized from the bone
marrow by administration of hematopoietic growth factors, or from the umbilical cord blood of newborn infants, a
rich source of HSCs. In most of the conditions in which HSC transplantation is indicated, the recipient is irradiated or
treated with high doses of chemotherapy to destroy the immune system (and sometimes, cancer cells) and to” open up”
niches in the microenvironment of the marrow that nurture HSCs, thus allowing the transplanted HSCs to engraft. A
problem that is unique to HSC transplantation is graft-versus-host disease (GVHD). GVHD occurs when
immunologically competent cells or their precursors are transplanted into immunologically crippled recipients, and
the transferred cells recognize antigens of the host and attack host tissues (mainly skin, liver, intestines, immune
system). It is seen most commonly in the setting of HSC transplantation but, rarely, may occur following
transplantation of solid organs rich in lymphoid cells (e.g., the liver) or transfusion of unirradiated blood (irradiation
of cellular blood components inactivates viable donor T-lymphocytes thereby preventing their proliferation). To try
to minimize GVHD, HSC transplants are done between donor and recipient that are MHC matched using precise DNA
sequencing-based methods for molecular typing of MHC alleles.

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