Chapter 11

Undesirable and altered immunity

 Immune Disorder
• An immune disorder is a dysfunction of the
immune system

• Immune dysfunction occurs as a result of

improper regulation that allows the immune
system to
– Either attack something it shouldn’t or
– Fail to attack something it should

• ID cause abnormally low activity or over activity

of the immune system
 There are three types of immunological
disorders

1. Hypersensitivity(including allergy)
2. Autoimmune disease
3. Immunodeficiency
 1. Hypersensitivity

• These result from inappropriate and overly active

immune responses to common innocuous env’t
Ag, such as : pollen,
food,
animal dander etc..
Based on mechanics involved and time taken for
the reactions; HSR reactions are four types :
– Type I: (Anaphylactic) Reactions
– Type II: (Cytotoxic) Reactions
– Type III: (Immune Complex) Reactions
– Type IV: (Cell-Mediated) Reactions
 Hypersensitivity reaction depends on:

o Chemical nature of allergen

o Route involved in sensitization i.e. inhalation,
ingestion, injection…
o Physiological state of individual / genetic potential
 Type I (Anaphylactic) Reactions

• It is also known as immediate hypersensitivity

• The reaction takes 15-30 minutes from the time

of exposure to the antigen

• Type I hypersensitivity is mediated by IgE

• The primary cellular component in this

hypersensitivity are mast cell or basophil
Common allergens associated with type I
hypersensitivity

Source: Kuby Immunology 2007 5th ed

 Type I Hypersensitivity
• Mechanism
– Allergen is recognized by naïve B cell
– B cell stimulated by T helper cell through IL4
– IgE specific for allergen is recognized by mast
cell
– Cross linkage of IgE on mast cells
– Mast cell degranulates
 Immediate (type I)
Type of Hypersensitivity
 Mechanism of type I hypersensitivity
Primary Generation
Allergen Individual IgE
Adhesion
Secondary IgE binds to the FceRI on mast cell and basophil

Allergen binds to the IgE on primed target cell

Crosslikage of FceRI

Degranulate and release the biological mediators

Preformed granule mediators New generated mediators

Histamine Bradykinin Leukotrienes PAF Prostaglandin D2

Dilate capillaries,increase permeability, increase mucus secretion, contract smooth muscle

Systemic anaphylaxis Skin Respiratory tract Degist tract

 Three classes of mediators derived from mast cells:

1. Preformed mediators stored in granules (histamine),

preformed cytokines (IL-1, IL-6) and Enzymes
– tryptase, chymase, cathepsin

2. Newly sensitized mediators:

leukotrienes C4, prostaglandins D2, platelets activating
factor (PAF)

3. Cytokines produced by activated mast cells, basophils

e.g. TNF, IL3, IL-4, IL-5 IL-13, chemokines
These mediators cause:

smooth muscle contraction,

mucous secretion
 bronchial spasm
vasodilatation,
vascular permeability and
edema
 Type I Reactions Can Be Systemic or Localized

Systemic anaphylaxis
• Is a shock-like and often fatal state whose onset
occurs within minutes of a type I HSR.

• A wide range of Ag have been shown to trigger

this reaction in susceptible humans, including
– venom from bee
– wasp, hornet, and ant stings;
– drugs, such as penicillin, insulin, and antitoxins;
seafood and
– nuts.
• If not treated quickly, these reactions can be
fatal.

• Epinephrine is the drug of choice for systemic

anaphylactic reactions.
 Localized anaphylaxis (atopy)
• In localized anaphylaxis, the reaction is
– Limited to a specific target tissue or organ,
– Often involving epithelial surfaces at the site of
allergen entry.
– Genetically predetermined

• The tendency to manifest localized anaphylactic

reactions is inherited and is called atopy.
• Atopic allergies include:
– Allergic rhinitis (hay fever)
– Asthma
– Atopic dermatitis (eczema)
– Food allergies
Type I Hypersensitivity:
Diagnostic tests

A. Skin tests- injections or scratchings

-Stim local Mast cells
-Produces P-K rxn (wheal and flare)
-Inexpensive and quick
-May sensitize one to new Ag’s
-May stim late-phase rxn in some

B. Immunoassays for serum IgE

-Radioimmunosorbent test (RIST)
-Radioallergosorbent test (RAST)
 Immunoassays for IgE
RIST

RAST
 Type II (Cytotoxic) Reactions
• Mediated, primarily, by antibodies of IgM or IgG
class and complement

• Affect a variety of organs and tissue and the

reaction time is minutes to hours.

• The Ag are normally endogenous, although

exogenous chemicals (haptens) that can attach to
cell membranes can also lead to type II HSR.
 Mechanism of Cytolysis

Cell lysis results due to :

1) Complement fixation to antigen antibody

complex on cell surface
• The activated complement will lead to cell lysis

2) Phagocytosis is enhanced by the antibody

(opsinin) bound to cell antigen leading to
opsonization of the target cell
 Mechanism….
3) Antibody depended cellular cytotoxicity (ADCC):
- Antibody coated cells
e.g. tumor cells, graft cells or infected cells can
be killed by cells possess Fc receptors

- The process different from phagocytosis and

independent of complement
- Cells most active in ADCC are:
NK, macrophages, neutrophils and eosinophils
• Examples of type II hypersensitive reactions

1. Transfusion Reactions
2. Hemolytic Disease of the Newborn
3. Drug-Induced Hemolytic Anemia
4. Autoimmune diseases

e.g. SLE, Hashimoto’s thyroiditis

An Example of Type II HSR
Hemolytic disease of the newborn
 Type III Hypersensitivity

Immune Complex Mediated Reaction

* When Ab (IgG or IgM) and antigen coexist immune
complexes are formed

* Immune complexes are removed by reticuloendoth.

syst.

* Some immune complexes escape phagocytosis

* Immune complexes deposited in tissues on the

basement membrane of blood vessels and cause
tissue injury
 Mechanism Of Tissue Injury
Immune complexes trigger inflammatory processes:

1) Immune complexes activate the complement

release anaphylatoxins (C3a, C5a)

stimulate
histamine release degranulation of basophiles and mast cells
2. Neutrophils are attracted to the site by immune
complexes and release lysosomal enzymes
which damage tissues and intensify the
inflammatory Process .

3. Platelets are aggregated with consequences

like release of histamine
 Clinical conditions of Type III Hypersensitivity
Diseases produced by immune complexes are those in
which antigens persists without being eliminated as:

a- Repeated exposure to extrinsic antigen

b- injection of large amounts of antigens

c- Persistent infections

d- Autoimmunity to self components

 Clinical Conditions…..

1- Arthus Reaction
2- Serum Sickness
3- Post-streptococcal glomerulonephritis
4- Hypersensitive pneumonitis (farmer lung)
 Type IV
Cell Mediated
Delayed Type Hypersensitivity
 Type IV (Cell-Mediated) Reactions

• DTH response does cause extensive tissue

damage

• In many cases the response also plays an

important role in defense against intracellular
pathogens and contact antigens
• The hallmarks of a type IV reaction are:
- the delay in time required for the reaction to
develop and
- the recruitment of MФ as opposed to
neutrophils, as found in a type III reaction

•MФ are the major component of the infiltrate that

surrounds the site of inflammation
Intracellular pathogens and contact antigens that induce
delayed-type (type IV) hypersensitivity

Source: Kuby. Immunology 2007 5 th ed).

 Phases of the DTH Response
I. Sensitization phase
• DTH response begins with an initial
sensitization phase of 1–2 weeks after primary
contact with an antigen

• During this period, TH cells are activated and

clonally expanded
• A variety of antigen-presenting cells have been
shown to be involved in the activation of a
DTH response, including:

– Langerhans cells
– Macrophages

• T cells activated during the sensitization phase

are CD4+, primarily of the TH1 subtype.
Efector phase
• A subsequent exposure to the Ag induces the
effector phase of the DTH response

• In the effector phase, TH1 cells secrete a

variety of cytokines that recruit and activate
MФ and other nonspecific inflammatory cells

• A DTH response normally does not become

apparent until an average of 24 hr after the
second contact with the Ag
• the response generally peaks 48–72h after second
contact

• The delayed onset of this response reflects the time

required for the cytokines to induce localized
influxes of macrophages and their activation

 DTH response is important in host defense against

parasites and bacteria that live within cells, where
circulating antibodies cannot reach them.
Overview of the DTH response

Source: Kuby. Immunology 2007 5 th ed).

Type IV Hypersensitivity Clinical Conditions

• Granulomatous lesions
• Contact Dermatitis
• Insulin dependant diabetes mellitus
• Auto immune diseases and graft rejection
 2.Autoimmune Disease
• This could be caused by a sudden inability to
distinguish between self and non self

• or by a misinterpretation of a self-component as
dangerous.

• The symptoms of autoimmunity differ, depending

on which tissues or organs are under attack
• Eg.MS is due to an autoimmune attack on a protein
in nerve sheaths in the brain and CNS that results in
neuromuscular dysfunction

• Crohn’s disease is an attack on intestinal tissues that

leads to destruction of gut epithelia and poor
absorption of food.

• One of the most common autoimmune disorders, RA,

results from an immune attack on joints of the hands,
feet, arms, and legs.
• Both genetic and environmental factors are likely
involved in the development of most autoimmune
diseases

• However, the exact combination of genes and

environmental exposures that favor the development
of a particular autoimmune disease are difficult to
pin down
• These diseases result from the destruction of self
proteins, cells, and organs by auto-Ab or self-
reactive T cells

• For example, auto Ab are the major offender in

Hashimoto’s thyroiditis, in which Ab reactive with
thyroid-specific Ag cause severe tissue destruction

• On the other hand, many autoimmune diseases are

characterized by tissue destruction mediated directly
by T cells.
• A well-known example is RA, in which self-
reactive T cells attack the tissue in joints, causing
an inflammatory response that results in swelling
and tissue destruction

• Other examples of T-cell-mediated autoimmune

disease include insulin dependent or Type 1
diabetes mellitus (T1DM) and multiple sclerosis
(MS).
IMMUNEDEFICIENCY DISORDERS
 Introduction
• Like any complex multicomponent system, the
immune system can be subject to failures of some
or all of its parts.
• These failures can have consequences. When the
system loses its sense of self and begins to attack
the host’s own cells, the result is autoimmunity.
• When the system errs by failing to protect the host
from disease causing agents, the result is
immunodeficiency.
• Two broad categories of immunodeficiency
disorders are:
1. primary immunodeficiency.
2. Secondary immunodeficiency
 1. Primary immunodeficiency

Immunodeficiency resulting from an inherited

genetic or developmental defect in the immune
system is called a primary immunodeficiency or
congenital immunodeficiency.

Congenital immunodeficiency syndromes are under

diagnosed.

Basic knowledge of embryology of immunity is

essential to understand most congenital syndromes
 1. Primary defects of Ab production

 Of all of the primary immunodeficiency

diseases, those affecting antibody production
are most frequent

 Selective absence of serum and secretory IgA is

the most common defect, with rates ranging
from 1/333 to 1/18,000 persons among different
races.
 X- linked agammaglobulinemia (XLA)

• Patients XLA, or Bruton agammaglobulinemia, have

- profound defect in B-lymphocyte development
- severe hypogammaglobulinemia
- absence of circulating B cells
- small to absent tonsils
- no palpable lymph nodes

• The abnormal gene in XLA maps to q22on the long

arm of the X chromosome and encodes the B-cell
protein tyrosine kinase Btk (Bruton tyrosine kinase)
 Common variable immunodeficiency

• hypogammaglobulinemia with phenotypically

normal B cells
• Later onset
• Equal sex distribution
• No identified molecular diagnosis
 Selective IgA deficiency

• Most common of primary antibody deficiencies

• Isolated or near absence of serum or secretary
IgA (<10mg)
• Occasionally associated with ill health
• Basic defect is unknown
 Treatment of B cell defects

• Antibiotics
• Intravenous immunoglobulins
• Stem cell transplant in XLP
 2. Primary defects of Cellular immunity

 In general, patients with defects in T-cell

function have infections or other clinical
problems that are more severe than in patients
with antibody deficiency disorders.

 These individuals rarely survive beyond infancy

or childhood
 Thymic hypoplasia ( DiGeorge syndrome)

• Dysmorphogenesis of 3rd
and 4th pharyngeal pouches

• Hypoplasia or aplasia of the

thymus and parathyroid
glands

• The diagnosis is often first

suggested by hypocalcemic
seizures during the neonatal
period
3. Severe combined immunodeficiency(SCID)

 The syndromes of SCID are caused by diverse

genetic mutations that lead to absence of all
adaptive immune function and, in some, a lack
of natural killer (NK) cells.

 Patients with this group of disorders have the

most Severe immunodeficiency.
 Combined immunodeficiency (CID)

• CID is distinguished from SCID by the presence of

low but not absent T-cell function.

• Similar to SCID, CID is a syndrome of diverse

genetic causes.

• Patients with CID have recurrent or chronic

pulmonary infections, failure to thrive, oral or
cutaneous candidiasis, chronic diarrhea, recurrent
skin infections
 Treatment of Combined defects

• Good supportive care including prevention and

treatment of infections is critical while patients await
more definitive therapy
• Immunoglobulins
• Transplant
 4. Disorders of phagocytic function

• Neutrophils are particularly important in protecting

the skin, mucous membranes, and lining of the
respiratory and GI tracts as part of the 1st line of
defense against microbial invasion.

• Disorders of phagocyte function should be

considered if results of initial screening tests are
normal and the patient has had recurrent or unusual
bacterial infections
 5. Complement deficiency
• is an ID of absent or suboptimal functioning of one of the
complement system proteins.
• The disorders can be divided into two categories:
1. Disorders of the proteins that act to inhibit the complement
system (such as C1-inhibitor) can lead to an overactive
response, causing conditions such as hereditary
angioedema and hemolytic-uremic syndrome.

2. Disorders of the proteins that act to activate the

complement system (such as C3) can lead to an underactive
response, causing greater susceptibility to infections.
 Clue about Nature of immunodeficiency
• Repeated pyogenic infections (tonsillitis, otitis media,
pneumonia, diss. Impetigo)
– Atrophied peripheral lymph nodes and tonsils
– B lymphocyte deficiency
• Severe mycotic infections, disease after live vaccine
– T lymphocyte deficiency
• Abscess formation (staph, serratia, aspergillus)
– Neutrophil deficiency
• Repeated Neisseria infection
– Complement deficiency
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 General categories of PIDs (Saunders & Mak,
2006)
1. SCID - low numbers/absence of T cells and sometimes of B cells;
lack of B cell functions due to T cell function impairment
2. T-PIDs - normal numbers of T, B, NK cells; T cells are non-
functional; B cell function may be affected
3. B-PIDs - B cells non-functional or absent; T and NK cells are
normal
4. DNA repair defects - low lymphocyte numbers
5. Lymphoproliferative disorders - mutations in death receptors or
ligands, or in caspase cascade; uncontrolled proliferation of T
and B cells
 General contd....

6. Phagocyte response deficiencies - defects in extravasation,

activation, function of phagocytes
7. IL-12 / IFN gamma axis - failure in macrophage (hyper-
activation)
8. Autoinflammatory syndromes - severe local inflammation and
prolonged periodic fevers with no obvious cause; lymphocyte
numbers are normal
9. Neutropenias - reduced level of neutrophils in circulation
10. Complement deficiencies - lack of complement activation; T and
B cells are normal
 2. SECONDARY IMMUNODEFICINCY
 Secondary immunodeficiency, also known as acquired
immunodeficiency, is the loss of immune function that
results from exposure to an external agent, often an
infection.

 Although several external factors can affect immune

function, by far the most well-known secondary
immunodeficiency is acquired immunodeficiency
syndrome (AIDS).
 Causes of secondary immunodeficiency
• Systemic disorders • Surgery
– Ig hypercatabolism • Malignancies
– Excess loss of Ig – B cell and plasma cell malignancies
– Renal insufficiency – Thymoma
– Extensive burns – Non Hodgkin’s lymphoma
• Drug induced • Infectious diseases
– – HIV
Cytotoxic
– Congenital rubella
– Glucocorticoids – Congenital toxoplasmosis
– Antimalaria agents – Epistein-Barr virus
– Captopril • Malnutrition
– Carbamazepine – PEM
– Zinc
– Phenytoin – Vitamins (pyridoxine, folic acid, vit A)
– Alcohol, opiates

70
 Acquired hypogammaglobulinemia

• Confused with common variable immunodeficiency

(genetic)
• Cause is unknown
• Sx –
– Recurrent infections
– Young adults
– Low but detectable level Ig
– T-cell usually normal
– Deficiency of Ig in new borne but improves
• Tx – Ig
71
 Agent induced immunodeficiency

• Cause is chemicals, biological agents

– Drugs for autoimmune diseases, steroids
– Post transplant – cyclosporine A
– Radiation therapy
• Higher risk of infection (chronic infections DM)
• Tx – close follow up and early treatment of infections

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Acquired Immunodeficiency Syndrome
 HIV
• 1981 - First AIDS cases in USA
– 5 PCP and 26 KS cases among homosexuals
– Subsequently it was detected also among IDU and
hemophilics
• 1983 - HIV was isolated from a pt with PGL
and demonstrated as the cause of AIDS in
1984
• 1985 - ELISA was developed and used for
detection of the epidemiologic scope

74
 Epidemiology

• Globally - 33.2 million (30.6 -36.1 mill.) are

PLHIV
• Sub-Saharan Africa has 22.5million cases, more
than half of the total (67.8%)
• Adults: 30.8 million [28.2- 33.6 million
• Women: 15.4 million [13.9– 16.6 million]
• Children under 15 years: 2.5 million [2.2 – 2.6
million]
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The virusGenome
-Gag – structural proteins
- pol – rev transcriptase
- env – envelop

Regulatory proteins
- tat – transactivator
transcrition
- rev – viral proteins
-Nef – down regulator

Structural proteins
- gp160 – envelop
-P24 , p17 – inner and outer
viral capsid
- p66, p51, p31 – enzymatic
-P6 and p7 – nucleic acid 77
 Overview of HIV life cycle

HIV life cycle:

1. Binding and Fusion
2. Entry
3. Reverse transcription
4. Integration
5. Viral RNA and protein expression
6. Assembly and budding
7. Maturation

HIV target cells:

CD4T cells,
Macrohpages,
Dendritic cells
80
 Role of T helper cells

• Normal count 700-1200cells/mcl

– Induction of CTL maturation and function
– Induction of Natural killer cells function
– induction of B cells differentiation and function
– activation of macrophages
– secretion of growth factors for lymphoid cells
– secretion of hematopoietic colony stimulating
factors
– central for both cell mediated and humeral immune
arms

81
 ID by HIV contd..
• Direct effect of viral component on Th cells
• Functional disturbance of CD4 (low Ag detection)
• Low IL-2 expression
• Alter Th homing (increase migration to LN)
• Apoptosis of Th via caspase-1 (not caspase-3)
• Cytopathic effect by CD8 cells
• Low production of immunomodulatory by Th
• Disturbing proper CD8 maturation
• Increase AAMQs, B cell hyperactivation
• NK= impaired cytolytic
 Immune reconstitution inflammatory
syndrome
 Development of clinical manifestations of a
previously sub-clinical opportunistic infection
and/or paradoxical worsening of active infection
despite appropriate treatment.
It occurs in 11-45% of HIV TB coinfected and on tx.
 Occurs usually within 3 months of starting ART
 Reflects a restored, protective, pathogen-specific
immune response,
Not ART treatment failure

83