Immunology

Immunopathology

The immune system is a complex and highly developed system, yet its mission is simple: to seek and kill invaders.
Innate (or natural) immunity: Non specific defenses or barriers to infection which are (in healthy people) always present.
Adaptive (or acquired) immunity: A response that is directed toward a specific pathogen and develops over time and has “memory” (reactivity changes with repeated exposure).
Innate Immunity Components
Physical
Barriers to infection e.g. skin
Flushing mechanisms e.g. coughing, urine flow
Chemical responses e.g. lysozyme in tears, complement
Cellular e.g. phagocytic cells (able to engulf and ingest material)
Specific Immunity Components
Humoral immune response using antibodies ……B-lymphocytes
Cell mediated immune response ….. T-lymphocytes

Major Histocompatibility Complex (MHC)

A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility. Also called HLA (Human Leukocyte Antigens) in humans
It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated
MHC genes products are classified into:
Class I antigens: are coded by 3 closely linked loci; A, B, and C; (HLA-A, HLA-B, HLA-C) these are present on all nucleated cells& platelets.
Class II antigens : are in the D region (HLA-DP, HLA-DQ, HLA-DR) and have a narrow distribution (mostly on mononuclear inflammatory cells; macrophages and dendritic cells).
Class III antigen : Complement system protein
HLA Antigens are like (finger prints ) on the cell surface.


Why are HLA important?
HLA matching is important in transplantation
HLA regulate some immune responses
Virus-infected cells with class I antigen are lysed by CD8+ cells that can recognize the virus-cell complex
Class II antigens help to induce CD4+ cells
HLA are associated with a variety of diseases, such as HLA B27 with ankylosing spondylitis, or HLA DR 2, DR3, and DR4 with autoimmune diseases.
Mechanisms of Immune Injury
Adverse reactions caused by immune mechanisms are termed hypersensitivity reactions (HSR). HSR classified into four types. Type I, II, and III require the active production of antibody by plasma cells. Type IV is mediated by the interaction of T cells and macrophages.
Type I (anaphylactic) hypersensitivity
Steps in the reaction
Immunoglobulin E (IgE) antibody production by IgE B cells is stimulated by antigen (Ag). The IgE antibody is then bound to the Fc receptors of mast cells and basophils.
On subsequent exposure, Ag (allergen) reacts with bound IgE antibody ( complement is not involved), resulting in degranulation of mast cells and basophils. This reaction requires bridging (cross-linking) of adjacent IgE molecules on the mast cells surface.
Degranulation results in histamine release, which increases vascular permeability. Various other substances are produced, many of which are vasoactive or smooth muscle spasm-inducing.
Chemotactic substances recruit eosinophils, resulting in tissue and peripheral blood eosinophilia.
Clinical examples
Allergic or atopic reactions, such as seasonal rhinitis (hay fever), allergic asthma, or urticaria.
Systemic anaphylaxis (anaphylactic shock) is a potentially fatal reaction, characterized by the rapid onset of urticaria, bronchospasm, laryngeal edema, and shock after exposure to offending antigen.
Hereditary angioedema is caused by deficiency of C1 esterase inhibitor; serum C4 is low and other complement components such as C3 are consumed.
Type II (Cytotoxic) hypersensitivity
1- Complement-fixing antibodies reacts directly with antigens that are integral components of the target cell. The interaction of complement with the cell surface results in cell lysis and destruction. Serum complement is characteristically decreased.
The Ags involved are usually localized to tissue basement membranes or blood cell membranes.
Clinical examples include autoimmune hemolytic anemia, hemolytic transfusion reaction, and hemolytic disease of the newborn (erythroblastosis fetalis), in which the antigens are components of red blood cell membranes; and Goodpasture syndrome (antiglomerular basement membrane antibody), in which the pulmonary alveolar and glomerular basement membranes are affected.
Pemphigus vulgaris caused by Abs against desmosomal protein that lead to disruption of epidermal intercellular junction.
2- Antibody-dependent cell mediated cytotoxicity (ADCC)
Antibody react directly with integral surface antigens of targeted cells.
The free Fc portion of the Ab molecule reacts with the Fc receptor of a variety of Cytotoxic leukocytes, most important NK cells. Other leukocytes, including monocytes, neutrophils, and eosinophils, also bear Fc receptors and can participate in ADCC.
The target cells are killed by the Fc receptor-bound Cytotoxic leukocytes. Complement is not involved.
3- Antibody-mediated cellular dysfunction
In some cases, Abs directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation. Thus, in myasthenia gravis, Abs against acetylcholine receptors in the motor end plates of skeletal muscles impair neuromuscular transmission with resultant muscle weakness. Conversely, Abs can stimulate cell function. In Graves disease, Abs against the thyroid stimulating hormone receptor stimulate thyroid epithelial cells and result in hyperthyroidism.


Type III (Immune complex) hypersensitivity
Is mediated by the deposition of Ag-Ab (immune) complexes, followed by complement activation and accumulation of polymorph nuclear leukocytes.
Immune complexes can involve exogenous Ags such as bacteria and viruses or endogenous Ags such as DNA
Immune complexes are most often removed by cells of the mononuclear phagocyte system without adverse effect. Pathologic immune complexes either form in the circulation and subsequently deposit in the tissues or form at extracellular sites where Ag has been planted (in situ immune complexes).
Immune complex-mediated injury can be systemic when complexes are formed in the circulation and are deposited in multiple organs or localized to particular organs (e.g., kidneys, joints, or skin) if the complexes are formed and deposited in a specific site.
The mechanism of tissue injury is the same regardless of the pattern of distribution; the immune complexes bind complement, which is highly chemotactic for neutrophils,. The neutrophils release lysosomal enzymes, resulting in tissue damage, which can also result from other substances released by neutrophils, including prostaglandins, kinin, and free radicals.
Immune complexes can also cause platelet aggregation and activate Hageman factor (factor XII) ; both of these reactions augment the inflammatory process and initiate microthrombi formation that contribute to the tissue injury by producing local ischemia.
During the active phase of the disease, consumption of complement decreases the serum levels.
Clinical examples
Serum sickness: is a systemic deposition of Ag-Ab complexes in multiple sites, especially the heart, joints, and kidneys. In the past, antibody containing foreign serum (most often horse serum) was administered therapeutically for passive immunization against microorganisms or their toxic products. Because of the danger of serum sickness, this mode of therapy is no longer employed.
Systemic Lupus Erythromatosus: is also an example of multisystem immune complex disease.
Arthus reaction: is a localized immune complex reaction that occurs when exogenous Ag is introduce, either by injection or by organ transplant, in the presence of an excess of preformed Abs.
Polyarteritis nodosa: is a generalized immune complex disease especially involving small and medium sized arteries.
Immune complex-mediated glomerular diseases: include poststreptococcal glomerulonephritis, membranous glomerulonephritis, and lupus nephropathy.
Type IV (cell-mediated ) hypersensitivity
Delayed hypersensitivity
Is exemplified by the tuberculin reaction, a localized inflammatory reaction initiated by the intracutaneous injection of tuberculin and marked by proliferation of lymphocytes, monocytes, and small numbers of neutrophils, with a tendency toward cellular accumulations about small vessels (perivascular cuffing). Induration (hardening ) results from fibrin formation.
Is also exemplified by contact dermatitis, which may result from either delayed hypersensitivity or direct chemical injury to the skin.
Involves the interaction of the T cell receptor of CD4+ lymphocytes with Ag, presented by macrophages, and with HLA class II antigens on macrophages, resulting in stimulation of antigen specific CD4+ memory T cells.
On subsequent contact with Ag, the CD4+ T memory cells proliferate and secrete cytokines.
IL-2 and other cytokines secreted by the CD4+ T cells recruit and stimulate the phagocytic activity of macrophages.
T- cell-mediated cytotoxicity
Is direct CD8+ T cell-mediated killing of target cells (typically tumor cells or virus-infected cells)
Target cell HLA class I Ags recognized as self Ags are also required
Specific target cell Ag is recognized by the T cell receptor of CD8+ lymphocytes.
Two principle mechanisms of Cytotoxic T lymphocyte killing have been demonstrated: 1- perforin-granzyme-dependent killing and 2- Fas-Fas ligand dependent killing.
Cytokines are not involved.


Transplantation Immunology
General considerations
For a successful graft, donor and recipient must be matched for ABO blood groups and, ideally; for as many HLA Ags as possible.
Adverse immune responses can be suppressed by immunosuppressant drugs, radiation, or recipient T cell depletion. However; these processes can result in clinically significant immunodeficiency.

Types of transplant rejection

Three basic patterns of graft rejection are well illustrated by rejection following kidney transplantation.

Hyperacute rejection

Is primarily Ab-mediated and occurs in the presence of preexisting Ab to donor Ag.
Most often occurs within minutes of transplantation.
Is a localized Arthus reaction marked by acute inflammation, fibrinoid necrosis of small vessels, and extensive thrombosis.
Acute rejection
Is primarily T cell mediated.
Generally occurs days to months after transplantation.
Is characterized by infiltration of lymphocytes and macrophages.
May, when Ab-mediated mechanisms are prominent, show evidence of arteritis with thrombosis and cortical necrosis.

Chronic rejection

Is primarily caused by Ab-mediated vascular damage.
May occur months to years after an otherwise successful transplantation.
Is characterized histologically by marked vascular fibrointimal proliferation, often resulting in a small, scarred kidney.
Is becoming more common with the success of immunosuppression in overcoming acute rejection.


Graft-versus-host disease
Is a significant problem in bone marrow transplantation because immunocompetent cells are transplanted in this procedure.
Can also caused by whole blood transfusion in patients with severe combined immunodeficiency.
Is characterized by the rejection of (foreign) host cells by engrafted T and B cells.
CD8+ T cells from graft directly damage host cells.
Cytokines from graft CD4+ T cells recruit macrophages, which damage host cells.
Clinical features include fever, rash, and hepatosplenomegally.
Principle target organs are liver, skin, and GIT mucosa.