 defined as an exaggerated or inappropriate state of normal immune response with onset of adverse effects on body 1. Autoimmunity:  reactions against self antigens.  Normally, immune system does not react against one’s own antigens, phenomenon c/d self tolerance,  When such self-tolerance fails, resulting in reactions against one’s own cells & tissues. Collectively, such reactions constitute autoimmunity & diseases cozd by autoimmunity k/a autoimmune diseases.

2. Reactions against microbes

3. Reactions against environmental antigens : e.g., pollens, animal danders, & dust mites, some metal ions & therapeutic +drugs. Such individuals are genetically predisposed for unusual immune responses to noninfectious.  4 types based on principal immune mechanism responsible for injury:

1. Immediate (type I) HS c/d allergy,  defined as a state of rapidly developing or anaphylactic type of immune response to an antigen (i.e. allergen) to which the individual is previously sensitised (anaphylaxis is the opposite of prophylaxis).

 Rxn appears within 15-30 minutes of exposure to antigen.  injury is caused by TH2 cells, IgE antibodies, mast cells.  Production of IgE antibody → immediate release of vasoactive amines & other mediators from mast cells; later recruitment of inflammatory cells  Protype disorder - Anaphylaxis; allergies; bronchial asthma (atopic forms) 2. Antibody-mediated (type II) HS –

 defined as reactions by humoral antibodies that attack cell surface antigens on specific cells and tissues and cause lysis of target cells.

 appears generally within 15-30 minutes after exposure to antigen.

 caused by Production of IgG, IgM → binds to antigen on target cell or fixed tissue → phagocytosis or lysis of target cell by activated complement or Fc receptors; recruitment of leukocytes

 Protype disease - Autoimmune hemolytic anemia; Goodpasture syndrome. 3. In immune complex–mediated disorders (type III hypersensitivity) :

 IgG & IgM antibodies bind antigens, usually in circulation & form antigen- antibody complexes that deposit in vascular beds and induce inflammation.

 Recruited neutrophils & monocytes produce tissue damage by release of lysosomal enzymes & generation of toxic FR.

 Deposition of Ag-Ab complexes → complement activation → recruitment of leukocytes by complement products and Fc receptors → release of enzymes & other toxic molecules

 Eg. Systemic lupus erythematosus; some forms of glomerulonephritis; serum sickness; Arthus reaction 4. Cell-mediated (type IV) hypersensitivity :

 caused mainly by immune responses in which T lymphocytes of TH1 & TH17 subsets produce cytokines  induce inflammation & activate neutrophils & macrophages coz tissue injury.

 CD8+ CTLs also may contribute to injury by directly killing host cells

 Activated T lymphocytes → (1) release of cytokines, inflammation and macrophage activation; (2) T cell–mediated cytotoxicity Perivascular cellular infiltrates; edema; granuloma formation; cell destruction

 Eg. Contact dermatitis; multiple sclerosis; type 1 diabetes; tuberculosis

 Antigen–antibody (immune) complexes  produce tissue damage  mainly by eliciting inflammation & complement activation

 Pathologic rxn is initiated when : i. Ag combines with Ab in circulation  form Ag- Ab complex  deposit in vessel wall ii. Less frequently, complexes may be formed at sites where antigen has been “planted” previously (called in situ immune complexes).

 Ag that form immune complexes may be :  Exogenous eg. foreign protein i.e. injected or produced by an infectious microbe, or  endogenous, if individual produces Ab against self Ag (autoimmunity)  Type III reaction is not tissue specific and occurs when antigen-antibody complexes fail to get removed by body’s immune system.

 3 types of etiologic factors precipitating type III reaction: 1. Persistence of low-grade microbial infection : Persistence of infection (antigen) & corresponding weak Ab response l/t chronic Ag-Ab complex formation fail to get eliminated from body fluidsdeposited in tissues e.g. in blood vessel wall, glomeruli, joint tissue etc.

2. Extrinsic environmental antigen. Exogenous Ag inhaled into lungs e.g. antigens derived from moulds, plants or animals combines with Ab in alveolar fluid & forms Ag-Ab complexdeposited in alveolar walls.

3. Autoimmune process : formation of autoantibodies against own tissue (self Ag) eg. circulating (e.g. IgA) or tissue derived (e.g. DNA) Immune complex mediated HS

Systemic immune complex disease local immune comlex disease ( Acute serum sickness) ( Arthus reaction )  Acute serum sickness is the prototype of a systemic immune complex disease b/c once a freq sequela to administration of large amounts of foreign serum (e.g.,serum from immunized horses used for protection against diphtheria).

 Recently, less freq  seen in individuals who receive Ab from other individuals or species, e.g. horse or rabbit antithymocyte globulin administered to deplete T cells in recipients of organ grafts

1. Formation of Immune Complexes :

introduction of a protein antigen

triggers an immune response

results in formation of Ab (1 week after injection of protein)

Ab are secreted into blood

react with Ag present in circulation & form Ag-Ab complexes. 2. Deposition of Immune Complexes :

circulating Ag-Ab complexes deposited in various tissues.

medium size complexes are formed when antigen is in slight excess are most pathogenic

immune complexes deposited at organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid

Mostly deposited in eg. glomeruli & joints. 3. Inflammation and Tissue Injury :

 immune complexes in tissue initiate an acute inflammatory rxn via complement activation & engagement of leukocyte Fc receptors.

 Approximately 10 days after Ag adm. C/f such as fever, urticaria, joint pain (arthralgia), lymph node enlargement, and proteinuria appear.

 resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, Glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in joints, and so on.

 Complement fixing Ab ( IgG/ IgM) & Ab that biond to leukocyte Fc receptors produces pathologic lesion of immune complex  Administration of single large dose of Ag  l/t acute serum sickness  lesions resolve d/t phagocytosis& degradation of the immune complexes.

 Repeated or prolonged exposure to Ag (eg. autoAb) chronic serum sickness eg. SLE  Principal morphologic manifestation of immune complex injury is acute vasculitis, associated with fibrinoid necrosis of the vessel wall and intense neutrophilic infiltration.

 Deposited immune complexes in kidney, by immunofluorescence microscopy appear as granular deposits of immunoglobulin &complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane  Model of local immune complex diseases is Arthus reaction, in which an area of tissue necrosis appears as result of acute immune complex vasculitis.  Experimentally this rxn is produced by injecting Ag into skin of previously immunized animal with preformed antibody.

 When Ag diffuses into vascular wall at site of injection, immune complexes form

 triggering the same inflammatory reaction & histologic appearance as in systemic immune complex disease.

 Arthus lesions evolve over a few hours and reach a peak 4 to 10 hours after injection & injection site develops edema & h’mg, occasionally followed by ulceration. Disease Antigen Involved Clinicopathological Manifestations 1. Systemic lupus Nuclear antigens (circulating or Nephritis, skin lesions, erythematosus “planted” in kidney) arthritis, others

2. Poststreptococcal Streptococcal cell wall antigen(s); Nephritis glomerulonephritis may be “planted” in glomerular basement membrane

3. Polyarteritis Hepatitis B virus antigens in some Systemic vasculitis nodosa cases

4. Reactive arthritis Bacterial antigens (e.g., Yersinia) Acute arthritis

5. Serum sickness Various proteins (e.g., foreign serum Arthritis, vasculitis, protein) (horse anti-thymocyte nephritis globulin)

Arthus reaction Various foreign proteins Cutaneous vasculitis (experimental