GOLLIS UNIVERSITY

DEPARTMENT OF MEDICINE

5 Diseases of the Immune System.

Pathology lecturer:- Dr. Hassan Abdiraman

 Immunity refers to protection against infections. The immune system is the collection of cells and molecules that are responsible for defending us against the countless pathogenic microbes in our environment.

 Deficiencies in immune defenses result in an increased susceptibility to infections, which can be life-threatening if the deficits are not corrected. On the other hand, the immune system is itself capable of causing great harm and is the root cause of some of the most vexing(difficult) and intractable diseases of the modern world. Thus, diseases of immunity range from those caused by "too little" to those caused by "too much or inappropriate" immune activity.

INNATE AND ADAPTIVE IMMUNITY .

Defense against microbes consists of two types of reactions; 1- Innate immunity (also called natural, or native immunity). 2- Adaptive immunity (also called acquired, or specific, immunity).

Innate immunity .
The major components of innate immunity are: Epithelial barriers of the skin Gastrointestinal tract Respiratory tract. Cells involved; Phagocytic leukocytes ( Neurophils and Macrophages).

Adaptive immunity .
Adaptive immunity is normally silent and responds (or "adapts") to the presence of infectious microbes by becoming active, expanding, and generating potent mechanisms for neutralizing and eliminating the microbes. The components are;
lymphocytes and their products

The terms "immune system" and "immune response" refer to adaptive immunity.

Types of adaptive immune responses:

a).Humoral immunity; mediated by soluble antibody proteins that are produced by B lymphocytes (also called B cells). b).Cell-mediated (or cellular) immunity; mediated by T lymphocytes (also called T cells)

 Antibodies provide protection against extracellular microbes in the blood, mucosal secretions, and tissues. T lymphocytes are important in defense against intracellular microbes.

CELLS AND TISSUES OF THE IMMUNE SYSTEM.

Lymphocytes.(B lymphocytes and T lymphocytes). Natural Killer Cells. Antigen-Presenting Cells or Dendritic Cells Lymphoid Tissues.

Lymphocytes.
All lymphocytes appear morphologically identical. Lymphocytes develop from precursors in the generative lymphoid organs. T lymphocytes are so called because they mature in the thymus. B lymphocytes mature in the bone marrow the demonstration of antigen receptor gene rearrangements by molecular methods (e.g., polymerase chain reaction, or PCR) is a definitive marker of T or B lymphocytes. Such analyses are used in classification of lymphoid malignancies.

T Lymphocytes.
Constitute 60% to 70% of the lymphocytes in peripheral blood. Major lymphocyte population in splenic periarteriolar sheaths. T cells do Not detect free or circulating antigens >95% of T cells recognize only peptide fragments of protein antigens. CD4 and CD8 are expressed on distinct T-cell subsets and serve as coreceptors for T-cell activation. CD4+ T cells are "helper" T cells because they secrete soluble molecules (cytokines) that help B cells to produce antibodies.

 CD8+ T cells can also secrete cytokines, but they play a more important role in directly killing virus-infected or tumor cells, and hence are called "cytotoxic" T lymphocytes (CTLs).

B Lymphocytes.
Bone marrow-derived. Comprise 10% to 20% of the circulating peripheral lymphocyte population. Also present in bone marrow and in the follicles of peripheral lymphoid tissues (lymph nodes, spleen, tonsils,
and other mucosal tissues).

Stimulation of follicular B cells leads to the formation of a central zone of large, activated B cells in follicles, called a germinal center. B cells are the only cell lineage that synthesize antibodies, also called immunoglobulins (Ig).

 After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies,the mediators of humoral immunity.

Five classes of Immunoglobulins(Ig):

IgG, IgM, and IgA constitute more than 95% of circulating antibodies. IgA is the major isotype in mucosal secretions. IgE is present in the circulation at very low concentrations and is also found attached to the surfaces of tissue mast cells IgD is expressed on the surfaces of B cells but is not secreted.

Natural Killer Cells.

Are lymphocytes that arise from the common lymphoid progenitor that gives rise to T and B lymphocytes. They do not have specificities as diverse as do T cells or B cells. NK cells use a limited set of activating receptors to recognize and kill molecules expressed; a) stressed or infected cells b) cells with DNA damage

Antigen-Presenting Cells.
APCs are dendritic cells (DCs), the major cells for displaying protein antigens to naive T cells to initiate immune responses, Effector Cells.

Effector Cells; NK cells are frontline effector cells because of their ability to rapidly react against "stressed" cells.

Lymphoid Tissues.
Generative (primary) organs;
(thymus and bone marrow)

Peripheral(secondary) lymphoid organs;

(lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues)

OVERVIEW OF NORMAL IMMUNE RESPONSES.

 Adaptive immune responses consist of sequential phases: a)Recognition of antigen by specific lymphocytes b)Activation of lymphocytes(consisting of their
proliferation and differentiation into effector cells).

c)Effector phase (elimination of antigen).

The response declines as antigen is eliminated, and most of the antigen-stimulated lymphocytes die by apoptosis. The antigen-specific cells that survive are responsible for memory.

Humoral Immunity: Activation of B Lymphocytes and Elimination of Extracellular Microbes.

HYPERSENSITIVITY DISEASES: MECHANISMS OF IMMUNE-MEDIATED INJURY.

Immune responses are capable of causing tissue injury and diseases that are called hypersensitivity diseases. This term originated from the idea that individuals who mount immune responses against an antigen are said to be "sensitized" to that antigen, and therefore, pathologic or excessive reactions are manifestations of "hypersensitivity."

 Immune responses may be inadequately controlled or inappropriately targeted to host tissues, and in these situations, the normally beneficial response is the cause of disease.

Causes of Hypersensitivity Diseases.

Autoimmunity Reactions against

microbes

(poststreptococcal

glomerulonephritis, rheumatic heart diseases, viral hepatitis).

Reactions against environmental antigens. The problem in these diseases is that the response is triggered and maintained inappropriately. Because the stimuli for these abnormal immune responses are difficult or impossible to eliminate.

Types of Hypersensitivity Diseases.

Immediate (Type I) Hypersensitivity.

Immediate hypersensitivity is a tissue reaction that occurs rapidly (typically within minutes) after the interaction of antigen with IgE antibody that is bound to the surface of mast cells in a sensitized host

Sequence of Events in Immediate Hypersensitivity Reactions.

Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates TH2 responses and IgE production. IgE binds to Fc receptors (FcRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic manifestations of immediate hypersensitivity.

Mast cell mediators.

Summary of the action of mast cell mediators in immediate hypersensitivity.

Clinical and Pathologic Manifestations.

The clinical manifestations may be local or systemic, and range from mildly annoying rhinitis to fatal anaphylaxis.

Antibody-Mediated Diseases (Type II Hypersensitivity).

Antibody-mediated (type II) hypersensitivity disorders are caused by antibodies directed against target antigens on the surface of cells or other tissue components.

Mechanisms of Antibody-Mediated Diseases.

Immune Complex Diseases (Type III Hypersensitivity).

Antigen-antibody (immune) complexes that are formed in the circulation may deposit in blood vessels, leading to complement activation and acute inflammation. The antigens in these complexes may be exogenous antigens, such as microbial proteins, or endogenous antigens, such as nucleoproteins.

Examples of immune complex-mediated diseases.

Systemic Immune Complex Disease.

The pathogenesis of systemic immune complex disease can be divided into three phases: 1) formation of antigen-antibody complexes in the circulation. 2) deposition of the immune complexes in various tissues 3) initiating an inflammatory reaction in various sites throughout the body

T-Cell-Mediated (Type IV) Hypersensitivity.

Two types of T-cell reactions are capable of causing tissue injury and disease:
1) delayed-type hypersensitivity (DTH), initiated by CD4+ T cells. 2) direct cell cytotoxicity, mediated by CD8+ T cells

Examples of T-cell-mediated(Type IV) hypersensitivity.

Granulomatous inflammation.

REJECTION OF TRANSPLANTS.
The major barrier to transplantation of organs from one individual to another of the same species (called allografts) is immunologic rejection of the transplanted tissue. Rejection is a complex phenomenon involving both cell- and antibody-mediated hypersensitivity reactions

Immune Recognition of Allografts

Rejection of allografts is a response to MHC molecules, which are so polymorphic that no two individuals in an outbred population are likely to express exactly the same set of MHC molecules (except, of course, for identical twins).

 There are two main mechanisms by which the host immune system recognizes and responds to the MHC molecules on the graft. A) Direct recognition. Host T cells directly recognize the allogeneic (foreign) MHC molecules that are expressed on graft cells. B) Indirect recognition. In this instance, host CD4+ T cells recognize donor MHC molecules after these molecules are picked up, processed, and presented by the host's own APCs(similar to physiologic response to microbial antigens).

Recognition and Rejection of Organ Transplants (Allografts).

The graft rejection response is initiated mainly by host T cells that recognize the foreign HLA antigens of the graft, either directly (on APCs in the graft) or indirectly (after uptake and presentation by host APCs).Types and mechanisms of rejection:
Hyperacute rejection. Preformed antidonor antibodies bind to graft endothelium immediately after transplantation, leading to thrombosis, ischemic damage, and rapid graft failure. Acute cellular rejection. T cells destroy graft parenchyma by cytotoxicity and DTH reaction. Acute vascular rejection. T cells and antibodies damage graft vasculature. Chronic rejection. Dominated by arteriosclerosis, this type is probably caused by T-cell reaction and secretion of cytokines that induce proliferation of vascular smooth muscle cells, associated with parenchymal fibrosis.

AUTOIMMUNE DISEASES

Immunological Tolerance.

Mechanisms of Autoimmunity

Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of protean manifestations and variable behavior. Clinically, it is an unpredictable, remitting and relapsing disease of acute or insidious onset that may involve virtually any organ in the body; however, it affects principally the skin, kidneys, serosal membranes, joints, and heart. Immunologically, the disease is associated with an enormous array of autoantibodies, classically including antinuclear antibodies (ANAs).

Epidemiology.
its prevalence may be as high as 1 case per 2500 persons in certain populations. Like many autoimmune diseases, there is a strong (approximately 9 : 1) female preponderance, affecting 1 in 700 women of childbearing age. Its usual onset is in the second or third decade of life.

Etiology and Pathogenesis .

The fundamental defect in SLE is a failure to maintain self-tolerance. Spectrum of Autoantibodies in SLE;
Antibodies have been identified against a host of nuclear and cytoplasmic components. Antiphospholipid antibodies. Antinuclear Antibodies.(Most commonly used clinically).

ANAs are directed against several nuclear antigens and can be grouped into four categories: 1) antibodies to DNA. 2) antibodies to histones. 3) antibodies to nonhistone proteins bound to RNA. 4) antibodies to nucleolar antigens.

Pathogenesis cont.

*The proposed classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person is said to have systemic lupus erythematosus if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.

Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease affecting many tissues but principally attacking the joints to produce a nonsuppurative proliferative synovitis that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis. Extra-articular involvement develops-for example, of the skin, heart, blood vessels, muscles, and lungs-RA may resemble SLE or scleroderma.

Epidemiology.
Prevalence of approximately 1%; it is three to five times more common in women than in men. The peak incidence is in the second to fourth decades of life.

Pathogenesis.