Disorders of ImmunityDisorders of Immunity

A- Mechanisms of immune- mediated injuryA- Mechanisms of immune- mediated injury

(Hypersensitivity Reactions)(Hypersensitivity Reactions)

B- Autoimmune DiseasesB- Autoimmune Diseases

C- Immunodeficiency DiseasesC- Immunodeficiency Diseases

D- AmyloidosisD- Amyloidosis

Hypersensitivity (Allergy, immune mediated injury)Hypersensitivity (Allergy, immune mediated injury)

-Hypersensitivity: A change in the tissue reaction following re-exposure Hypersensitivity: A change in the tissue reaction following re-exposure to antigento antigen

-Antigen Antigen (first time)(first time) No harmful effect + stimulation of formation of No harmful effect + stimulation of formation of specific antibodiesspecific antibodies

(Second time)(Second time) Ag will react with the specific antibody fixed on the cells Ag will react with the specific antibody fixed on the cells

Cellular damage with severe inflammatory reaction = hypersensitivityCellular damage with severe inflammatory reaction = hypersensitivity

OROR

Hypersensitivity is a state of altered Hypersensitivity is a state of altered immune responsiveness in which a immune responsiveness in which a severe and harmful immune reaction severe and harmful immune reaction occurs on exposure to the antigen.occurs on exposure to the antigen.

IMMUNE MECHANISMS OF TISSUE INJURY IMMUNE MECHANISMS OF TISSUE INJURY Hypersensitivity reactions/diseasesHypersensitivity reactions/diseases

Classified into 4 types based on the Classified into 4 types based on the immune mechanisms of tissue injury:immune mechanisms of tissue injury:

Type IType I, , Type IIType II, , Type IIIType III and and Type IV.Type IV.

Type I HypersensitivityType I HypersensitivityAnaphylaxis; Anaphylactic ReactionAnaphylaxis; Anaphylactic Reaction

Mast cell proliferation and IgE production by plasma Mast cell proliferation and IgE production by plasma cellscells

IgE bound mast cellsIgE bound mast cells Recurrent exposure: Recurrent exposure:

-- Mast cell degranulation-- Mast cell degranulation

-- Vasodilation-- Vasodilation

-- Bronchoconstriction, etc. -- Bronchoconstriction, etc.

ECF = eosinophil chemotactic factorNCF = neutrophil chemotactic factorPAF = platelet-activating factor

Phases of Type I HypersensitivityPhases of Type I Hypersensitivity

-Initial (rapid) responseInitial (rapid) response:: within 5-30 min after within 5-30 min after re-exposure with resolution within 30 min, re-exposure with resolution within 30 min, mediated by mediated by primary mast cell mediatorsprimary mast cell mediators

- Second (delayed) phase:Second (delayed) phase: 2-8 hours later, 2-8 hours later, lasts for days and characterized by an intense lasts for days and characterized by an intense infiltration by inflammatory cells and tissue infiltration by inflammatory cells and tissue damage. It is mediated by secondary mast cell damage. It is mediated by secondary mast cell mediators.mediators.

Type I HypersensitivityType I HypersensitivityA sequence of EventsA sequence of Events

Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Systemic anaphylaxis: Systemic anaphylaxis: -- Acute asthma-- Acute asthma

-- Laryngeal edema-- Laryngeal edema

-- Diarrhea-- Diarrhea

-- Urticaria-- Urticaria

-- Shock (Anaphylactic shock)-- Shock (Anaphylactic shock)

Typically follows oral administration pf allergen as:Typically follows oral administration pf allergen as: E.g.: penicillin allergyE.g.: penicillin allergy E.g.: bee sting allergyE.g.: bee sting allergy Antisera, Drugs, HormonesAntisera, Drugs, Hormones

Type I Hypersensitivity ReactionType I Hypersensitivity ReactionClinical ManifestationsClinical Manifestations

Local anaphylaxisLocal anaphylaxis (Atopy): (Atopy):

- - Food allergiesFood allergies-- Urticaria or Hives-- Urticaria or Hives-- Asthma-- Asthma-- Hay fever/ allergic rhinitis-- Hay fever/ allergic rhinitis (Ragweed pollen)(Ragweed pollen)-Wheal reaction: Local area-Wheal reaction: Local areaOf erythema and edema due to Of erythema and edema due to

Intradermal injection of antigen in Intradermal injection of antigen in sensitized individual.sensitized individual.

Type I Hypersensitivity ReactionType I Hypersensitivity ReactionClinical ManifestationsClinical Manifestations

EosinophilEosinophil

Type II HypersensitivityType II Hypersensitivity

1-1- Complement Dependent Reaction:Complement Dependent Reaction: Antibody is directed against a tissue antigenAntibody is directed against a tissue antigen

-- e.g. RBC or basement membrane-- e.g. RBC or basement membrane Ag-Ab complexes activate complement leading to Ag-Ab complexes activate complement leading to

cell lysis or extracellular tissue damagecell lysis or extracellular tissue damage

Two mechanisms:Two mechanisms:A- Direct LysisA- Direct LysisB- Opsonization (Enhanced B- Opsonization (Enhanced phagocytosis).phagocytosis).Ex:Ex:-Transfusion reactionsTransfusion reactions-Hemolytic anemiasHemolytic anemias-Goodpasture,s disease of the Goodpasture,s disease of the kidneykidney

Type II HypersensitivityType II Hypersensitivity2- Antibody- Dependent Cell- 2- Antibody- Dependent Cell- Mediated Cytotoxicity (ADCC)Mediated Cytotoxicity (ADCC)

Targets are lysed by Targets are lysed by

non- sensitized cells non- sensitized cells with Fc receptors.with Fc receptors.

NK (natural killer) NK (natural killer) cells, monocytes, and cells, monocytes, and granulocytes then granulocytes then bind to the bind to the immunoglobulin Fc immunoglobulin Fc receptors and causes receptors and causes damagedamage

Type II Hypersensitivity ReactionType II Hypersensitivity Reaction3- Antibody- mediated cellular dysfunction3- Antibody- mediated cellular dysfunction

Myasthenia gravisMyasthenia gravis:: Antibodies Antibodies against acetylcholine receptors against acetylcholine receptors in motor end plate of SM impair in motor end plate of SM impair neuromuscular transmission & neuromuscular transmission & result in muscle weekness.result in muscle weekness.

Grave's disease (thyrotoxicosis):Grave's disease (thyrotoxicosis): Anti-TSH receptor antibody stimulate Anti-TSH receptor antibody stimulate

thyroid and result in hyperthyroidism. thyroid and result in hyperthyroidism.

Antibodies directed against cell Antibodies directed against cell surface receptors impirs or surface receptors impirs or dysregulate function without dysregulate function without causing cell injury. Ex:causing cell injury. Ex:

Type II HypersensitivityType II HypersensitivityAntibody-Mediated InjuryAntibody-Mediated Injury

Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Myasthenia gravisMyasthenia gravis

(Acetylcholine receptor (Acetylcholine receptor antibody)antibody)

Type II Hypersensitivity ReactionType II Hypersensitivity Reaction

Clinical ManifestationsClinical Manifestations

Transfusion and transplant reactionsTransfusion and transplant reactions Rhesus incompatibility between Rh-negative mother Rhesus incompatibility between Rh-negative mother

and Rh-positive fetus (and Rh-positive fetus (erythroblastosis fetaliserythroblastosis fetalis))

Erythroblastosis fetalisErythroblastosis fetalis Elevated Rh antibody titers Many immature RBCs in blood Excess bilirubin from RBC breakdown -- Hyperbilirubinemia (yellow tissues) First baby = OK, because IgM cannot cross placenta, after that, IgG takes over Progressive anemia, ischemia, death Brain damage from bilirubin: kernicterus Prevention: Rh- mother gets anti-D immunoglobulin after birth (covers antigenic sites on baby’s RBCs in mother’s blood Rx: phototherapy of baby (breaks bilirubin)

Immune hydrops from Rh hemolysisImmune hydrops from Rh hemolysis

Type II Hypersensitivity ReactionType II Hypersensitivity Reaction

Clinical ManifestationsClinical Manifestations

Autoimmune hemolytic anemiaAutoimmune hemolytic anemia AgranulocytosisAgranulocytosis ThrombocytopeniaThrombocytopenia Pemphigus vulgarisPemphigus vulgaris PemphigoidPemphigoid

(Cicatricial pemphigoid)(Cicatricial pemphigoid)PemphigoidPemphigoid

PemphigoidPemphigoid

Type III HypersensitivityType III HypersensitivityImmune Complex MediatedImmune Complex Mediated

Ag-Ab complexes is formed either in circulation or extravascular.Ag-Ab complexes is formed either in circulation or extravascular. Tissue damage primarily through complement activationTissue damage primarily through complement activation Exogenous antigen: i.e. bacterial, viralExogenous antigen: i.e. bacterial, viral Endogenous antigen: i.e. DNA antigensEndogenous antigen: i.e. DNA antigens C3b acts as an opsoninC3b acts as an opsonin C5a acts as a chemoattractant for neutrophilsC5a acts as a chemoattractant for neutrophils -- Acute Necrotizing Vasculitis-- Acute Necrotizing Vasculitis

Type III HypersensitivityType III HypersensitivityImmune Complex MediatedImmune Complex Mediated

Immune complexes can be deposited:Immune complexes can be deposited: I- Systemically (Serum sickness type) I- Systemically (Serum sickness type) due due

to administration of large amount of foreign serum. to administration of large amount of foreign serum.

II- Locally (Arthus reaction type)II- Locally (Arthus reaction type)Common clinical findings:Common clinical findings:

FeverFever

UrticariaUrticaria

ArthralgiaArthralgia

LymphadenopathyLymphadenopathy

ProteinuriaProteinuria

I- Systemic Immune Complex I- Systemic Immune Complex DiseaseDisease

Immune Complex Mediated (Type III) DamageImmune Complex Mediated (Type III) DamageSystemicSystemic

Acute (single large dose of Ag exposure):Acute (single large dose of Ag exposure): Acute serum sicknessAcute serum sickness Poststreptococcal glomerulonephritisPoststreptococcal glomerulonephritis

Chronic (persistent/repeated Ag exposure):Chronic (persistent/repeated Ag exposure): Systemic lupus erythematosusSystemic lupus erythematosus Rheumatoid arthritisRheumatoid arthritis Membranous glomerulonephritisMembranous glomerulonephritis -- Inciting antigens = unknown-- Inciting antigens = unknown

Immune Complex Immune Complex Deposition in Deposition in GlomerulusGlomerulus

Type III HypersensitivityType III Hypersensitivity

II- Local Immune Complex Disease (Arthus Reaction)II- Local Immune Complex Disease (Arthus Reaction)

•It is defined as a localized area of tissue necrosis It is defined as a localized area of tissue necrosis resulting from acute immune complex vasculitis.resulting from acute immune complex vasculitis.

• local formation and deposition of immune complexeslocal formation and deposition of immune complexes

• Planting of antigen within a particular tissue (e.g., renal Planting of antigen within a particular tissue (e.g., renal glomeruli) with subsequent formation of immune glomeruli) with subsequent formation of immune complexescomplexes

• Produced experimentally by intracutaneous antigen Produced experimentally by intracutaneous antigen injection in a sensitized host carrying antibody= Ab in injection in a sensitized host carrying antibody= Ab in excessexcess

• Large immune complexes deposition Large immune complexes deposition complement complement and coagulation cascades activation and platelets and coagulation cascades activation and platelets aggregation lead to fibrinoid necrosisaggregation lead to fibrinoid necrosis

• Superimposed thrombosis may cause tissue necrosis.Superimposed thrombosis may cause tissue necrosis.

Type IV Hypersensitivity (Cell- Mediated)Type IV Hypersensitivity (Cell- Mediated)-Initiated by specifically sensitized T lymphocytes rather than antibodies.Initiated by specifically sensitized T lymphocytes rather than antibodies.

- Includes Includes Delayed-type hypersensitivityDelayed-type hypersensitivity and and T-cell mediated cytotoxicityT-cell mediated cytotoxicity..

1) Delayed-Type Hypersensitivity (DTH):1) Delayed-Type Hypersensitivity (DTH):•Principle pattern of response in T.B., fungi, protozoa & parasites, & graft Principle pattern of response in T.B., fungi, protozoa & parasites, & graft rejection and tumor immunity.rejection and tumor immunity.

• Mediated by CD4 cells of the Th1 that secrete specific cytokines after Mediated by CD4 cells of the Th1 that secrete specific cytokines after encounter the processed antigen in association with class II major encounter the processed antigen in association with class II major histocompatibility complex.histocompatibility complex.

• The induction of CD4 response is facilitated by IL-12 that secreted by The induction of CD4 response is facilitated by IL-12 that secreted by macrophages that have engulfed microbes or other antigenmacrophages that have engulfed microbes or other antigen

• cytokines mediate injury by recruiting and activating antigen-nonspecific cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages. monocytes and macrophages.

• with persistence of non-degradable antigens, the initial non-specific with persistence of non-degradable antigens, the initial non-specific infiltrate of T cells and macrophages is replaced by collections of infiltrate of T cells and macrophages is replaced by collections of macrophages that transform into epitheliod cells forming local macrophages that transform into epitheliod cells forming local granuloma. granuloma. So a granuloma is a special form of DTH.So a granuloma is a special form of DTH.

Type IV HypersensitivityType IV HypersensitivityDelayed Hypersensitivity ReactionDelayed Hypersensitivity Reaction

CD4+ T lymphocytes + class II HLA CD4+ T lymphocytes + class II HLA moleculesmoleculesNumerous cytokinesNumerous cytokinesMacrophagesMacrophages

Anti-CD4 AntibodiesAnti-CD4 Antibodies

Granuloma FormationGranuloma Formation

Multinucleated Multinucleated giant cellgiant cell

2) T cell-Mediated Cytotoxicity2) T cell-Mediated Cytotoxicity-Sensitized Sensitized CD8+ cytotoxic T lymphocytes (CTLs)CD8+ cytotoxic T lymphocytes (CTLs) is is the principle pattern of response in this type of response.the principle pattern of response in this type of response.

- e.g. a- Viral infection b- Tumor cells c- Transplant rejectione.g. a- Viral infection b- Tumor cells c- Transplant rejection

- Class I MHC molecules bind to intracellular viral peptides and present Class I MHC molecules bind to intracellular viral peptides and present them to CD8+ T lymphocytes.them to CD8+ T lymphocytes.

•Mechanism of of CTL Killing:Mechanism of of CTL Killing:

1- Perforin- granzyme- dependent killing:1- Perforin- granzyme- dependent killing:

Perforin and granzyme are soluble mediators of the CTLs that Perforin and granzyme are soluble mediators of the CTLs that induce apoptosis of the target cells.induce apoptosis of the target cells.

2- Fas- Fas ligand- dependent killing2- Fas- Fas ligand- dependent killing::

Activated CTLs express Fas ligand (a molecule with homology to Activated CTLs express Fas ligand (a molecule with homology to TNF) which binds to Fas on target cells that leads to apoptosis.TNF) which binds to Fas on target cells that leads to apoptosis.