IMMUNOPATHOLOGY

NORMAL IMMUNE RESPONSE

OVERVIEW OF IMMUNE SYSTEM Immunity is a state where an individual is protected against a particular dx. Such individual is resistant to dx cos of: formation of humoral antibodies or development of cellular immunity or development of both humoral and cellular immunity or other mechanisms such as viral infection interferon activity in

Cellular comp. : neutrophils, Natural Killer cells (NKCs) The complement cascade

Macrophages,

Triggered directly by the invading organism (alternate pathway) or by Antibodies(Abs) formed directly in the course of specific immune response The Complements in turn plays an impt. Role in modulating role in regulating cellular immunity Macrophages function as Phagocyte Antigen presenting cells(APC): impt role in triggering specific immune response mediated by T- & B-lymphocytes Mediating cellular immunity Regulating fxn of Ab-producing B cells as well as that of macrophages and NK cells

Normally the immune system protects against agents that r foreign or non-self However, abnormal situations may occur in: Immunodeficiency state: individual is susceptible to infection and possibly tumor Hyperactive immune state /system: theres overwhelming allergic rxn to a foreign substance. Such individual r said to be hypersensitive Autoimmunity: where in the immune system loses its ability to distinguish self from non-self against individual tissue and cells. DIVISION OF IMMUNE SYSTEM: INNATE/ NATURAL/ NAVE/ NON-SPECIFIC IMMUNE SYSTEM ADAPTIVE/ ACQUIRED/ SPECIFIC IMMUNE SYSTEM

ADAPTIVE IMMUNITY:
There r 2 forms: Cellular and Humoral Immunity CELLULAR COMPONENTS: r T- & B-lymphocytes Display antigenic specificity: by means of antigen-specific receptor on their surface that recognize only 1___. Unprimed ones r extremely small in number

INNATE IMMUNITY:
First line of defense cos: the actions of its component do not depend on prior sensitization to or priming by the antigen present on their target cell (microbes or tumor cells) and They do not possess the fine antigen specificity that is characteristic of the adaptive or specific immune responses. E.g. a macrophage can wet its appetite by ingesting a wide variety of antigenically distinct bacteria or viruses at its 1st encounter. It has 2 componentS: Humoral component: Complements which include chemotactic subst, opsonins, MAC,

Primed ones r large in number: when challenged with foreign antigen(Ag), they divide and expand (clonal expansion; Takes few days to weeks b4 the process is completed) to handle the offending organism Fights against intracellular microbes HUMORAL COMPONENT: are the Immunoglobulins (Igs) produced by Plasma cells (differentiated B lymphocytes) that fights against extracellular microbes and their toxins

CELLS AND TISSUES OF THE IMMUNE SYSTEM LYMPHOCYTES MACROPHAGES NATURAL KILLER CELLS DENDRITIC CELLS

Unlike B cells, it cannot be activated by soluble Ag. There4 APC must present processed form of the Ag to the T cell in order to induce a cell-mediated immunity Thus, during d Ag presentation, TCR binds to Ag presented by (the polymorphic portion of) the MHC on the surface of the APC; CD4 binds to d nonpolymorphic portion of Class II MHC, while CD8 binds to non-polymorphic portion of class I MHC molecule on the APC, when the TCR recognizes d Ag, the CD4 OR CD8 co-receptor initiates signals that are necessary for activation of the T cells.

T- LYMPHOCYTES ORIGIN: Derived from immature precursors in the thymus ANATOMIC SITES of mature Nave T cells: Blood: where they constitute circulating lymphocytes 60-70% of

Thus, CD4+ helper T cells can recognize and

T-cell zone in peripheral lymphoid organs such as Paracortical regions of Lymph nodes and periarteriolar zone of the spleen Reason for locating in these organs: these cells express receptors for the chemo-attractants, cytokines (chemokines), that r produced only in these regions. It Expresses Ag specific T-cell Receptor (TCR) TCR in 95%, and TCR in 5% of T cell population TCR = disulphide linked heterodimer of & polypeptide chain each having a variable (Ag binding) region and a constant region ); TCR also = + polypeptide chain heterodimer TCR Exhibits diversity that is generated by somatic rearrangement of TCR GENES, that occurs during development of the T-cells in the thymus, and serve as a (i) molecular marker of T-cell lineage and (ii) a distinguisher of polyclonal (nonreactive/non-neoplastic) T-cell proliferations from monoclonal (neoplastic) T-cell proliferations (i.e.

respond to Ags displayed only by MHC-II molecules, whereas CD8+ cytotoxic T cells recognize Ags displayed by MHC-I molecules
Activated T cells then secrete cytokines (cytk). One of d cytk, IL-2, causes self-proliferation, generating large num. of the Ag specific lymphocyte (autocrine effect). Some of these cells differentiate into: effector cells that perform the fxn of eliminating the Ag that started the response; Memory cells that r long-lived and r poised to respond rapidly to repeated encounter Supressor cells: T-cells also Have 2 fxnally distinct population of CD4+ helper-T cell (HTC): HTC-I or TH1 cells: synthesizes and secrete IL-2 and IFN- (but not IL-4 or IL-5); facilitates (i)delayed hypersensitivity, (ii) macrophage activation and (iii) synthesis of opsonizing and complement fixing Abs (such as IgG2A in mice) all of which r actions of IFN- HTC-II or TH2 cells produces IL-4, IL-5 and IL-13 (but not IL-2 or IFN-); aids in synthesis of other classes of Igs, notably IgE, (mediated by IL-4 & IL13) and in the activation of eosinophils (mediated by IL-5) CD8+ T CELLS: fxns as cytotoxic cells to kill other cells BUT similar to CD4+ T cells, they can secrete cytk primarily IL-2 and INF- of HTC-I

analysis of antigen receptor gene rearrangements is a valuable assay for molecular marking T-cell lineage & detecting lymphoid tumors)
It also expresses a num. of non-polymorphic function associated molecules (a.k.a Accessory molecules/coreceptors) in conjunction with the TCR, during T cell development in the thymus. They include: CD2, CD3, CD4 (in Helper T Cells), CD8 (in cytotoxic T cells), intergrins, and CD28. CD4 and CD8 r expressed in 2 mutually exclusive subsets of T cells: CD4 in 60% and CD8 in 30% of mature T cells (so, CD4:CD8 = 2:1)

B LYMPHOCYTES Develop from immature precursors in the bone marrow ANATOMICAL SITE: Blood: Mature B cells are 1020% of circulating lymphocytes Lymphoid tissue in: spleen, tonsils, extra-lymphatic organs (like GIT), Lymph nodes (in superficial cortex), spleen (in white core). Here they r aggregated in the form of lymphoid follicles (which on activation develop staining germinal centre) that occupy the B cell zone of these organs Reason for locating in these organs: the B cells express receptors for chemokines produced in the follicle

Responses to protein Ags require help from CD4+ T cells (HTCs) HTCs activate B cells by engaging CD40, a member of the TNF-receptor family and by secreting cytokines This interaction is essential for B cell maturation and secretion of IgG, IgA and IgE Abs. Ig secretions is mediated by cytk frm HTCs

MACROPHAGES (Mphs) Dominant cells in chronic inflammation One of the components of mononuclear phagocyte system (or RE system) RES consist of closely related cells of bone marrow including blood monocytes and tissue MPhs Tissue Mphs r diffusely scatterd in C.T. or located in organs such as liver (Kupfer cells), spleen (sinus histiocytes), brain (micorglia), bone (osteoclast)

They Express Ag specific B cell receptors (which r IgM and IgD) on the surface of all mature, naive B cells These receptors have a unique antigen specificity, derived from somatic rearrangements of Ig genes. Thus, as in T cells,

analysis of Ig gene rearrangements is useful for molecular marking of B-lineages and identifying monoclonal B-cell tumors
After antigenic stimulation, B cells mature in plasma cells that secrete Igs, mediators of humoral Immunity.

Derived from common precursors of in the bone marrow that give rise to blood monocytes that circulate in blood for abt a day b4 migrating to extravascular tissue to differentiate in Mphs, whose life(or life-span) can be months/years. Extravasation of Monocytes, Occurs quite early during Acute inflammation & in 48hrs, these cells constitute the predominant cell type in that tissue is governed by the same factors that cause neutrophil emigration (i.e. Adhesion molecules & chemical mediators with chemotactic nd activating properties

They Also expresses co-receptors, Ig & Ig, a heterodimer of the 2 non-polymorphic proteins. Similar to CD3 proteins of TCR, Ig & Ig do not bind but are essential for signal transduction through the Ag receptor non-polymorphic molecule

Also expresses other essential for B cell fxn:

(i) Complement receptors, (ii) Fc receptors & (iii) CD40 CD21 (OR complement receptor-2 CR2) is a receptor for Epstein-Barr virus (EBV) & hence EBV readily infect B cells.

express an array of specific cell surface molecules that are important for their host defense functions. MHC-II molecules, CD14 (a receptor that binds bacterial lipopolysaccharide and can trigger cell activation), several types receptors, toll-like receptors, of Fc immunoglobulin

Are activated by Protein and non-protein Ags END result: differentiation into Ab-secreting cells (plasma cells) which reside in lymphoid organs and mucosal tissue; some migrate to bone marrow and live there 4 several yrs Secreted Abs enter mucosa and the blood and r able to neutralize and eliminate the Ags

adhesion molecules and a variety of cytokine receptors that participate in regulating monocyte/macrophage function

r ACTIVATED by various stimulants including cytks like INF- secreted by sensitized T lymphocytes & NKCs, Bacterial toxins and other mediators END result: increase in cell size and level of lysosomal enz. more active metabolism greater ability to phagocytize and kill ingested microbes. Tissue injury & fibrosis (OR chronic inflammation) if activity of the activated Mph is unchecked

3) Expression of chemokine receptors that recruits the dendritic cells to the T-cell zones of lymphoid organs, in response to microbes, where they r ideally located and present antigens to T cells. 4) Expression of high level of MHC-II molecules needed for presenting antigens to and activating CD4+ T cells.

Follicular dendritic cells Present in the germinal centers of lymphoid follicles in the spleen and lymph nodes (hence their name) Bears Fc receptors for IgG and receptor for C3b (opsonin) and so and can trap Ag bound to Abs or complement proteins. Play a role in humoral immune responses by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen, thus improving the quality of the antibody produced.

DENDRITIC CELLS R of 2 types, each with different functions and both having dendritic cytoplasmic processes (hence their name) Interdigitating dendritic cells A.K.A Dendritic cells Follicular Dendritic cells

NKCs make up approx. 10% to 15% of peripheral blood lymphocytes and do not express TCRs or cell surface Ig Morphology: Larger than small lymphocytes Contain abundant granules; hence are Granular Lymphocytes azurophilic called Large

Interdigitating (Dendritic) Cells Most important APC For initiating against Ag primary immune response

Features accounting for this function: 1) Location in the right place to capture Ags like: Underneath Epithelia surfaces, the common site of entry of microbes and foreign Ag In interstitia of all tissues where Ag may b produced With the Epidermis: Langerhans cells epidermal

Are part of the innate immune system They r endowed with ability to kill a variety of infected and tumor cells, without prior exposure to or activation by these microbes or tumors This ability makes them an early line of defense against viral infections and, perhaps, some tumors.

2) Expression of many receptor for capturing and responding to microbes and other organisms

Are commonly identified by Two cell surface molecules, CD16 and CD56. CD16 is an Fc receptor for IgG, and it confers on NK cells the ability to lyse IgG-coated target cells. This phenomenon is known as anti-bodydependent cell-mediated cytotoxicity (ADCC).

HYPERSENSITIVITY REACTIONS (hps rxn) INTRODUCTION and DEFINITION It is the adverse immune response to Ags OR an immune response that leads to tissue injury or disease GENERAL FEATURES 1. It is elicited by both Exogenous antigens (food, drugs, dust, pollen, microbes, chemicals and many blood products used in chemical practice) and Endogenous Ags (or Self-Ags or Autologous Ags, to cause Autoimmune dx). 2. Some of these immune rxns r triggered by homologous Ags that differ among individuals of different genetic background (i.e. isoantigens isomers of an Ag). Transfusion rxns and Graft rejection r examples of immunologic disorders evoked by homologous Ags 3. The development of hypersensitivity diseases (both allergic and autoimmune disorders) is often associated with the inheritance of particular susceptibility genes (HLA and NonHLA Ags). 4. It reflects an imbalance between the effector mech-anisms of immune responses and the control mechanisms that serve to normally limit such CLASSIFICATION OF HYPERSENSITIVITY RXN TYPE I HYPERSENSITIVITY Hypersensitivity Immediate

~ is a rapid immunologic reaction occurring within minutes after the combination of an antigen with antibody bound to mast cells in individuals previously sensitized to the antigen. Also called ALLERGY The Ag eliciting this rxn: ALLERGEN. The Antibody (that is bound to FC receptors on the mast cell and Basophils) to which the Allergen binds is IgE 2 forms: System Hps Rxn and Localized hps Rxn Systemic rxn/Systemic Anaphylaxis/ Generalized Anaphylaxis; the immediate response, that follows intravenous injection of foreign Ag (antisera, hormone, enz., polysaccharides, drug,) to which the host has been sensitized. Example: Systemic Anaphylaxis (immediate response involving smooth muscles and capillaries throughout the body of a sensitized individual) Characterized by vascular shock, widespread edema and difficulty in breathing

 Local Immediate Hps rxn/Local Anaphylaxix: It is the immediate, transient response that is limited to the area surrounding the site of entry of the Ag. i.e. this rxn Varies depending on port of entry of Ag (like on skin, thru eye, resp. airway,) Characterized by Cutaneous swelling (Skin allergy) Hay fever Bronchial asthma Allergic gastroenteritis (food poisoning) Occurs In 10-20% of the population E.g. Ectopic allergy localized rxn to common environmental allergens such as pollen, animal danola, house dusts and food materials, Specific Dx include: Urticaria, Angioedema, Allergic Rhinitis, some form of Asthma 2 PHASES: Immediate/initial Phase & Late/second Phase rxn Initial Phase o Within 5 30 min after exposure o CAUSED by release of histamine, chemotactic factors for eosinophils, proteases, from IgE triggered Mast cells o Characterized by vasodialation and bronchoconstriction o Depends on the location, smooth muscle spasms or glandular secretion Late Phase o Sets in 2 24 hrs later without additional exposure to Ag o CAUSED by synthesis & release of PGs and Leukotrienes by the IgE triggered Mast cells o Characterized by Infiltrations of tissue with Eosinophils, neutrophils, monocyte, CD4+ T cells, as well as Tissue Degradation

In addition, TH2 cells (as well as mast cells and epithelial cells) produce chemokines that attract more TH2 cells, as well as other leukocytes, to the reaction site.

TYPE II HYPERSENSITIVITY REACTION (Antibody Mediated) ~ is a rxn caused by antibodies that react with antigens (intrinsic and/or Exogenous Ags) present on cell surfaces or in the extracellular matrix. FEATURES:

STEPS in the development of HPs rxns: see diagram below

NOTE: IL4: essential for turning off the IgE producing B cells and for sustaining TH2 development. IL-4 causes plasma cells to switch from IgM to IgE synthesis. IL5: activate Eosinophils which are effectors of Type I hypersensitivity IL13: promotes IgE production and acts on epithelial cells to stimulate mucus secretion

a. Mediated by IgG and IgM b. Cells involved: Phagocytes and NK cells 3 MECHANISMS: 1. OPSONIZATION and COMPLEMENT and FC receptor mediated PHAGOCYTOSIS (a.k.a Antibody mediated OPSONIZATION & PHAGOCYTOSIS)

2. COMPLEMENT and FC receptor mediated INFLAMMATION (Antibody mediated INFLAMMATION) 3. ANTIBODY mediated cellular DYSFUNCTION

i. ii.

glomerulonephritis, vascular rejection in organ grafts iii. Goodpasture syndrome iv. Bullous skin diseases

Antibody mediated PHAGOCYTOSIS

OPSONIZATION

&

ANTIBODY mediated cellular DYSFUNCTION

a. Here Ab deposited against a cell surface causes neither cell destruction nor inflammation but a change in the cells fxn. b. E.g. Myasthenia gravis (Abs binds to Ach receptors, impairing Neuromuscular transmission and causing muscular weakness); Graves dx (Abs bind to TSH receptors in thyroid gland, causing hyperthyroidism); Pemphigus vulgaris (Abs deposited against desmosome, disrupting intercellular adhesions in epidermis and leading to formation of skin vesicles or gully).

a. Abs (IgG + IgM) binds to Ags intrinsic to the body cells, causing the Classic Pathway activation of complement system that leads to i. Formation of MACs that disrupts membrane integrity by drilling holes through the lipid bilayer, thereby causing osmotic lysis of the cells. E.gs are seen in autoimmune hemolytic anemia, Erythroblastosis Foetalis and Transfusion rxn ii. Formation of OPSONIN, by-product of the pathway, which coats the cells, thus attracting phagocytes that hv receptors for these opsonins. E.gs are seen Certain types of autoimmune hemolytic anemia and some drug reactions

End result: phagocytosis of the cells

b. Antibody-dependent cellular cytotoxicity (ADCC) is another Ab mediated destruction of cells that does not require fixation of complements but rather, the activity of Cytolytic Leukocytes (which include Monocytes, Neutrophils, eosinophils and NK cells). These effectors cells Phagocytize & kill cells coated (or opsonized) with low conc. of antibodies (also called Specific or immune Opsonins), particulary IgG, They recognize the Ab-coated cells via their Fc receptors that bind to the Fc portion (or domain) of these Abs

Antibody mediated INFLAMMATION

a. Caused by Ab deposited in structural connective tissues e.g. basement membranes and extracellular matrix. b. The resultant injury is due to inflammation and not due to phagocytosis c. Deposited antibodies activate complement, generating by-products, such as chemotactic agents (mainly C5a), which direct the migration of polymorphonuclear leukocytes and monocytes, and anaphylatoxins (C3a and C5a), which increase vascular permeability. These leukocytes are activated by binding to the Abs via their Fc receptors and so, release injurious substances like enzymes and reactive O2 metabolites with resultant damage to the tissue. d. E.gs of Type I hypersensitivity due to INFlammation are

TYPE III HPS RXN (Immune Complex Mediated rxn) Here, immune complexes (Antigen-antibody complexes) r formed which are deposited in tissues where they elicit an inflammatory rxn and cause tissue injury. THE ABS INVOLVED: IgG and IgM and, occasionally, IgA THE AGS INVOLVED: r either Exogenous Ag like foreign particles, bacteria, streptococcal antigens, hepatitis B virus, and heroin OR Endogenous Ag: self-components which may be circulating Ags present in the blood or Agenic (or immunogenic) component of ones own cells and tissues, immunoglobulins and nuclear antigens

Clinical

features: Urticaria, Fever, General lymphadenopathy, Edema, Arthritis + joint pain, Proteinuria and severe Glomerulonephritis
LOCAL IMMUNE COMPLEX DX Prototype E.gs: Arthus Rxn a form of Type I hypersensitivity demonstrated experimentally by intracutaneous injection of an antigen into an individual that has been previously sensitized and has specific Abs against the Ag. The Ag diffusing into the blood vessels binds to the preformed Ab forming the immune complex that deposits/precipitate in walls of these vessels.

Here, u see that this deposition prevents the immune complex from travelling far to other tissue. So the resulting injury mediated by this complex is Local within the skin
Resulting vascular injury is mediated by complement fixation, followed by recruitment and activation of polymorphonucleic cells that phagocytize the deposits and release of their tissue-damaging mediators like proteases, Arachidonic acid products and O2 radicals (same mechanism as in Serum sickness). Arthus lesion develops over a few hrs and reaches a peak, 4-10 hrs after injection

THE IMMUNE COMPLEXES formed are either Circulating Immune complexes formed in the blood vessels and deposited on the vascular wall In situ Immune complexes that r formed at extravascular sites.

EFFECTOR CELLS: Polymorphonucleic cells & the immunocompetent cells 2 FORMS: Systemic Immune complex dx & Local immune complex dx SYSTEMIC IMMUNE COMPLEX DX Prototype Example: Acute SERUM SICKNESS Serum sickness is an acute, self-limited disease that typically occurs 6 to 8 days after injection of a foreign serum or serum protein, with both local and systemic reactions such as:

Clinical Features: erythema, edema, hemorrhage,

and necrosis

MORPHOLOGY OF IMMUNE COMPLEX INJURY a. Acute necrotizing inflammation (a.k.a necrotizing vasculitis) with necrosis of the vessel wall and intense neutrophilic infiltrations. b. Fibrinoid necrosis which hv a smudgy eosinophilic appearance: caused by immune complexes, + complement + plasma protein DXs OF TYPE III HPS RXN: 1. 2. 3. 4. Serum sickness Systemic lupus erythematosus (SLE) Polyarteritis nodosa Acute (OR Acute post-streptococcal) glomerulonephritis 5. Membranous nephropathy Difference btw type I hps and Arthus rxn:

Pathogenesis: is in 3 phases
i. Formation of immune complexes: introduction or Ag in the body leads to interaction with immunocompetent cells (Tand Blymphocytes) and a later release of Abs into the blood, 6-8 days after injecting the Ag. These Abs (which were not preformed) react with Ags to form Ag-Ab complexes. ii. Deposition of Immune Complexes: the immune complex are transported via the circulation, to many tissues where they r deposited. iii. Acute inflammatory rxn by the immune complex that causes Tissue injury. How? look

i. ii.

below Arthus rxn

Type I hps rxn occurs immediately; Arthus rxn, occurs within hrs Cells involved: mast cell & eosinophils (type I hps); all leucocytes (arthus rxn)

iii. iv.

Abs involved: IgE (type I hps): IgG & IgM (arthus) In Type I hps rxn, immune complex is formed on the mast cells; in Arthus rxn, immune complex is formed in circulation

TYPE IV HPS RXN (T-Cell Mediated OR Delayed Hps rxn) Mediators/Initiators: Ag-activated (sensitized) lymphocytes (CD4+ and CD8+ T cells) 2 types/Forms: Delayed-Type Hypersensitivity and Immune Inflammation - CD4+T cellmediated hypersensitivity Direct cell-mediated cytotoxic - CD8+ T cellmediated cytotoxity Hypersensitivity and Immune T-

Gross Morphology: Reddening and induration (hardening) of the site appears 8-12 hrs and reach a peak in 24-48 hrs and thereafter gradually subsides Microscopic Morphology o Initial Accumulation of perivascular lymphocytes & monocytes (a.k.a Perivasuclar Cuffing): these mononuclear cells surround around small veins and venules producing a perivascular cuffing with certain persistent and non-degradable Ags. o 2-3 weeks later, Granulomatous inflammation: Granuloma (Epitheloid cells surround by a collar of lymphocytes) is formed: lymphocytes r replaced by Mphs which inturn transform into epitheloid cells

Another Eg.: Contact dermatitis that result from either delayed hps or direct chemical injury to the skin

Delayed-Type Inflammation

Direct Cell-Mediated Cytotoxicity Effector cells: CTL (cytotoxic T Lymphocytes) the CD8+ T lymphocytes that mediate killing of target cells (typically Tumor cells or Virus-infected cells) Cytokines are not involved 2 main Mechanisms: a. perforin granzyme dependent killing b. Fas-Fas ligand dependent killing The perforin and granzymes are preformed mediators contained in the lysosome-like granules of CTL. Perforins perforates the plasma membrane of the target cell that are under attack by CD8+ lymphocytes thereby drilling hole into the membrane. The granzymes r then delivered into the target cells via the perforin-induced pores. Once in the cell the granzyme activate caspases which induce apoptosis of the target cells. In addition, the perforin pores allow H2O to enter the cell, thus causing osmotic lysis. FAS dependent Killing also induces apoptosis of the target cells but by different mechanism. Activated CTL express Fas ligand in molecules that is homologous to TNF that can bind to Fas expressed on target cells.

Its induced by environmental and self-antigens; initially thought to be induced by only environmental Ags Can be the cause of chronic inflammatory dx Mediated by T-lymphocytes; as such, adaptive immune system plays a central role in inflammation. Are responsible for many (not all) Autoimmune dxs, when the T cells reacts against self-Ags. In some of these T cellmediated autoimmune diseases, CD8+cells may also be involved.

Mechanism:
The TCR of CD4+ lymphocytes interact with the Ag, presented by APCs, and with HLA-II Ags on mphs, resulting in stimulation of Ag-specific CD4+ memory T cells. On subsequent contact with antigen, the CD4+ memory T cells proliferate and secrete cytokines. IL-2 and other cytokines secreted by the CD4 + T cells recruit and stimulate the phagocytic activity of macro phages

A classic example is tuberculin rxn produced by intracutaneous injection of tuberculin in a previously sensitized individual. Morphology of tuberculin rxn

10

AUTOIMMUNE DISEASES AUTOIMMUNITY immune rxn against self-antigen. Antibodies involved: Autoantibodies found in Serum of apparently normal individuals, particularly in older age groups. Innocuous (harmless) Abs formed after damage to tissue and may serve a physiologic role in the removal of tissue breakdown products

- Generalized OR Systemic Autoimmune dxs: o Systemic Lupus Erythematosus: in which a diversity of Abs directed against DNA, platelets, RBCs and Protein phospholipid complexes result in widespread lesions throughout the body. o Rheumatoid arthritis o Systemic sclerosis

Antigens involved: Self-Ags/autoantigens which are recognized as non-self if modified by infection, inflammation, or complexing with a drug. Antigens usually isolated from the immune system which are exposed by trauma or inflammation and become recognized as foreign. Examples include thyroglobulin, lens protein, and spermatozoa. A foreign antigen that shares a common structure with a host antigen

An abnormal autoimmune response to self-antigens implies a loss of immune (or immunologic) tolerance i.e. the body cannot tolerate Self & and there is loss of suppressor T cell control over B cell fxn.

IMMUNOLOGIC TOLERANCE Immunologic tolerance is a condition or state wherein an individual is incapable of developing an immune response to a specific Ag. Self-tolerance refers to lack of responsiveness to an individuals own antigens, and it underlies our ability to live in harmony with our cells and tissues. 2 Forms of Tolerance; CENTRAL TOLERANCE PERIPHERAL TOLERANCE

3 requirements for classifying autoimmune dx OR 3 features of autoimmune dx: a) the presence of an immune reaction specific for some self-antigen or self-tissue b) evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance c) The absence of another well-defined cause of the disease. However, Autoimmunity could result from tissue injury caused by T cells or antibodies that react against self-Ag. The spectrum of Autoimmunity has 2 extremes: on one end is Organ specific autoimmunity; on the other end is the generalized autoimmunity. In the middle is Goodpasture syndrome. - Organ specific Autoimmune dx. Examples: o type I Diabetes Mellitus: in which the autoreactive T cells and Abs attach specific cells of the pancreatic islet o Multiple sclerosis: autoreactive t cells react against CNS myelin o Addisons dx: immune destruction of adrenal cortex o Pernicious anemia: immune destruction of Parietal cells in the stomach o Hashimoto's thyroiditis: immune destruction of the thyroid

CENTRAL TOLERANCE Refers to death (lesion) of self-reactive T- & BLymphocyte clones during their maturation in the central/primary lymphoid organ (Thymus and Bone) Evidence show that T-lymphocytes that bear receptor for self-Ag undergo apoptosis within the thymus during the process of cell maturation It is proposed that many autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic APCs in association with self-MHC molecules and can, therefore, be recognized by potentially selfreactive T cells. A protein called AIRE (autoimmune regulator), present in medullary thymic epithelial cells (mTEC)

mediate the transcription of many self-Ags that r secreted (by these same thymic cells) in order to
stimulate expression of receptors for these Ags by the T-cells. Those developing T cells that express high affinity receptors for such Self-Ag are negatively selected or deleted (by apoptosis) and there4, the peripheral T-cell pool are lacking in self-reactive Tcells.

11

Mutations in AIRE gene are the cause of an autoimmune polyendocrinopathy (A disease usually caused by insufficiency of multiple endocrine glands) Some immature T-cells that encounter self-Ag in the thymus develop into regulatory T-cells. As with T-cells, clonal deletion is also operative in Bcells. When developing B cells encounter a membrane bound Ag within the bone marrow, they undergo apoptosis. However, clonal deletion of Self-reactive lymphocytes is not perfect. Many self-Ags may not be present in the thymus, hence, T-and B- cells bearing receptors for Self Ag escape into the periphery. B cells bearing self-Ag receptors for Ags (like Thyroglbulin, collagen & DNA) can be found in the peripheral blood of an individual. PERIPHERAL TOLERANCE Self-reactive T-cells that escape intra-thymic ve selection can cause tissue injury unless they are deleted in the peripheral tissue.

receptor. Evidence suggests that the inhibitory/suppressive activity of these cells may be mediated by the secretion of immunosuppressive cytokines such as IL-10 and TGF-, which inhibit lymphocyte activation and effector functions. DELETION BY ACTIVATION-INDUCED CELL DEATH: CD4+T cells that recognize self-antigens may receive signals that promote their death by apoptosis. This process has been called activationinduced cell death, because it is a consequence of Tcell activation. CLONAL

ANTIGEN SEQUESTRATION: 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. This is believed to be the case for the testis, eye, and brain, all of which are called immune-privileged sites (areas of Physiological barriers) 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.

MECHANISM OF ELIMINATING AUTOREACTIVE TCELLS FROM the PERIPHERY

ANERGY: refers to prolonged or irreversible functional inactivation of lymphocytes, induced by encounter with antigens under certain conditions. If the self-Ag is presented by competent APCs that do not bear the co-stimulators (that supposed to bind to the co-receptors on the Lymphocytes) a negative signal is delivered, and the lymphocytes becomes anergic. Since most dendritic cells in normal tissue weakly expresses or do not express co-stimulatory molecules, many of these auto-reactive TLymphocytes will become anergic once they recognize specific self-antigens displayed by these dendritic cells. Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter selfantigen in peripheral tissues, especially in the absence of specific helper T-cells, the B-cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death. SUPPRESSION BY REGULATORY T CELLS: Regulatory T cells develop mainly in the thymus, as a result of recognition of self-antigens, but they may also be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that constitutively express CD25, the -chain of the IL-2

Mechanisms of Autoimmunity Autoimmune dx results when self-tolerance is lost or by-passed 2 factors relevant to the development of autoimmune dx: 1. inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and 2. environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes Role of Susceptibility Gene (HLA and MHC genes) Best characterized susceptibility genes HLA and MHC gene Postulation: the presence of particular MHC alleles affects the negative selection of T cells in the thymus or the development of regulatory T cells but there is little proof for either possibility. However, many people inherit MHC genes that disease-associated but still have normal MHC molecules capable of presenting self-antigens.

12

Therefore, the presence of particular MHC alleles is not, by itself, the cause of autoimmunity In several autoimmune dxs e.g. SLE, Type I D.M., many non-MHC genes hv bin shown to be involve.

Role of infection 2 mechanisms have be postulated to relate infection with A.I. dx o Infections may up-regulate the expression of costimulators 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. o 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

Once an autoimmune disease has been induced it tends to be progressive, sometimes with sporadic relapses and remissions (on & off), and the damage becomes inexorable (continuous and irreversible).

13