genpathImmun

8/9/2019 genpathImmun

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Immunopathology

Ma. Minda Luz M. Manuguid, M.D.Ma. Minda Luz M. Manuguid, M.D.


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Cells of the ImmuneResponseCells of the ImmuneResponse

T-Lymphocytes

Null cells

B Lymphocytes Plasma cells

Macrophages

Others: Eosinophils, Basophils & Mast cells, Fibroblasts,

Endothelial cells, Dendritic (Langerhans)cells, Neutrophils


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LymphocytesLymphocytes


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Eosinophil BasophilMonocyte

Neutrophil

Platelets


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cells of the immune response:cells of the immune response:

TL

ymphocytesTL

ymphocytes T lymphocytes/ T cells:

Responsible for Cellular Immunity

all are CD3+thymus-derived70-80% of peripheral blood lymphocytesin interfollicular & paracortical areas of lymph

nodesin periarteriolar sheaths of the spleen


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TLymphocyt

es

TLymphocyt

es

Subtypes:Cytotoxic T cells CD8+ - capable of Antigen-directed

killing in delayed hypersensitivity reactions; organtransplant rejection; tumor immunity; viral/slow

bacterial immunityHelper T cells CD4+ - regulatory: help immunologic

cells to respond properly to Antigen Suppressor T cells CD8+ - suppress Antibody

production by B lymphocytesSecretions: Lymphokines = Interleukins (IL) 2, 3, 4, 5, 6 &

gamma interferon (INF)


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BLymphocyt

es

BLymphocyt

es

B lymphocytes/ B cells: responsible for Humoral Immunity 15% of peripheral blood lymphocytes in germinal centers & superficial cortices of lymph nodes in lymphoid follicles of the white pulp of the Spleen in the Bone marrowwith surface immunoglobulins: pre-B cells: heavy

chains; immature B cells: IgM --- IgD --- IgG, IgA, IgE


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Plasma c

ells

Plasma c

ells

Plasma cell

converted B lymphocyte capable of producing

immunoglobulins in large

numbers


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immunoglobulinsimmunoglobulins

Immunoglobulins/Antibodies:

Fc constant region;

Fab variable region binds Ag


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immunoglobulin structureimmunoglobulin structure

Immunoglobulins/

Antibodies:

IgA: secretoryantibodyIgG

IgMIgEIgD


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Null c

ells

Null c

ells

Null cells

Characteristics:

Large, with granular cytoplasmNo surface TCR or IgGSubtypes:NK (natural killer) cells cytolytic even without

purposeful immunization; same targets ascytotoxic T cellsK (killer) cells possess Fc receptors mediate

Antibody-dependent killing


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Monocyt

es/M

acrophage

sM

onocyte

s/M

acrophage

s

Mononuclear Phagocyte System all arephagocytes; produce monokines IL1(interleukin 1) &INF (alpha interferon)

Blood monocytesTissue histiocytes/macrophages

PAMs pulmonary alveolar macrophages Kupffer cells of the liver

Microglia/Mesoglia of the CNS Sinus histiocytes of the lymph nodes Osteoclasts of bone


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Basophils &

Mast c

ells

Basophils &

Mast c

ells

Basophils characterized by basophilic cytoplasmic

granules that contain histamine, heparin,

chemotactic factors & SRS A

Mast cells tissue counterpart of the basophil

cytoplasmic granules are metachromatic


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The Immune Response:The Immune Response:oth

ere

le

me

ntsothe

re

le

me

nts

The Complement system -

Plasma factors

Vasoactive aminesArachidonic acid metabolites -

Platelet-activating factor

Histocompatibility antigens -


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TheComplement SystemTheComplement System Classical Pathway-produces anaphylatoxins C3a, C4a,

C5a & leads to the formation of the C5b6789 complex(MAC)

Anaphylatoxins cause smooth muscle contraction,IgE-mediated basophil & mast celldegranulation, & vascular permeability.

C5b,6,7,8,9- membrane attack complex- lysesbacterialplasmamembranes

Alternative Pathway- triggered by bacterial endotoxin-produces C3a & C5a but not C4a

C5a is also chemotactic for neutrophilsC3b is an opsonin


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ArachidonicAcidMetabolitesArachidonicAcidMetabolites

Arachidonic Acid Metabolites/Eicosanoids Cyclooxygenase pathway- inhibited by Aspirin &

Indomethacin Prostaglandins :

PGD2, PGE2, PGF2a- vasodilators

PGI2 (Prostacyclin)- vasodilator; anti-platelet aggregation

Thromboxane (TXA2)- vasoconstrictor; PAF

Lipooxygenase pathway

Leukotrienes :LTC4, LTD4, LTE4 slow-reacting substances of anaphylaxis

LTB4 chemotactic for neutrophils


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Arachidonic acidMetabolitesArachidonic acidMetabolites


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HistocompatibilityAntigensHistocompatibilityAntigens

Human Leukocyte Antigens (HLA) a group of antigenspresent on the surface of nucleated body cells that allowthe immune system to distinguish self from nonself

gene products of the major histocompatibility complex(MHC) located on chromosome 6, short arm (p); have beenshown to have a strong influence on humanallotransplantation, transfusions in refractory patients, andcertain disease associations

The chance of two individuals having identical HLAmolecules on alllociis very low, except for siblings, whohave a 25% chance of being HLA-identical


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HistocompatibilityAntigensHistocompatibilityAntigens 3 major Class IHLA genes:

HLA-A, HLA-B and HLA-C (minor genesare HLA-E, HLA-F and HLA-G).

HLA Class I gene products combine with2-Microglobulin protein to form afunctional receptor on most nucleated cellsof the body

Recognized by cytotoxic T lymphocytes;restrict CD8+ cellsAntigenic targets in transplant rejection


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Class IIHLA genes

HLA-DP, HLA-DQ, HLA-DR; on surface ofmacrophages, B cells, activated T cells,endothelial cells, & dendritic Langerhans cells

Ags combine to form heterodimeric ()protein receptors that are typically expressed on

the surface ofantigen presenting cellsCritical to foreign Ag recognition by T cells;restrict CD4+ T cells


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The most intensely studied HLA genes are the nine

so-called classical MHC genes: are Class Igenes ,

HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1,

HLA-DRA, andHLA-DRB1.

additional HLA antigens in humans, HLA-DM and

HLA-DO, are important in loading the antigenic

peptides generated from pathogens onto the HLAmolecules ofantigen-presenting cell.


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When a foreignpathogen enters the body, specificcells called

antigen-presenting cells (APCs) engulf the pathogen through a

process calledphagocytosis. Proteins from the pathogen are

digested into small pieces (peptides) and loaded onto HLA antigens

(specificallyclass IIMHC). They are then displayed by the APCs for

certain cells of the immune system calledT cells, which then produce

a variety of effects to eliminate the pathogen.

Through a similar process,proteins (both native and foreign, such as

the proteins ofviruses) produced inside most cells are displayed onHLA antigens (specificallyclass IMHC) on the cell surface. Infected

cells can be recognized and destroyed by components of the

immune system.


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ImmunopathologyImmunopathology

Immunodeficiency= diminished function of the Immune

system

Genetic

Acquired Histotoxicity= immunologic mechanisms of tissue damage

Acute hypersensitivity reactionsCytotoxic reactions Immune complex disordersDelayed hypersensitivity reactions

Autoimmunity= loss of tolerance to self antigens


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Immunodeficiency disordersImmunodeficiency disorders Congenital

B cell: Brutons X-linked agammaglobulinemia transient hypogammaglobulinemia of infancy; selective IgA deficiency(1 in 700 live births)

T cell: DiGeorge syndrome congenital absence of the thymus chronic mucocutaneous Candidiasis autosomal recessive

Both T & B cell:

SCID (severe combined immunodeficiency) X-linked orautosomal recessive Acquired

AIDS(Acquired ImmunoDeficiency Syndrome)


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SevereCombinedSevereCombinedImmunoD

eficie

ncyImmunoDe

ficie

ncy

Boy in a plastic bubble


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Acquired ImmunoDeficiency SyndromeAcquired ImmunoDeficiency Syndrome

definition: (+) for HIV Ab + at least 1 life-threatening

opportunistic infection orKaposis sarcoma

etiology: HIV human immunodeficiency (retro)virus that

preferentially attacks helper T lymphocytes; acute infectionis transient mononucleosis-like is followed by persistent

generalized lymphadenopathy

ARC(Aids-related complex)= fever, weight loss, diarrhea,

marked in CD4+ cells


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Pathology ofAIDSPathology ofAIDS

Lymphadenopathy persistent, generalized, painless

Follicular hyperplasia, plasma cellsInterfollicular depletionGeneralized follicular involution lymphocyte

depletion; medullary fibrosis; vascularproliferation

Opportunistic infections viruses: CMV, EBV, HSV, HBV,

HZV, HPV; protozoa: ; fungi: ; bacteria: Neoplasms oral & anorectal cancer; tongue, rectum CA;

Kaposisarcoma; lymphoma; leukemia


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Kaposis sarcomaKaposis sarcoma


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Immunologic mechanisms ofImmunologic mechanisms of

Tissu

edamag

eTissu

edamag

e Type Ireaction: IMMEDIATE HYPERSENSITIVITY:antigen reacts with cell-bound antibody, usuallyIgE

Type IIreaction:ANTIBODY-MEDIATED CYTOTOXICITY:

cytotoxic antibodies IgG orIgM lyse target cells Type IIIreaction: IMMUNE COMPLEX DISEASE:

circulating Ag-Ab complexes are deposited in tissuescomplement activiation tissue injury

Type IVreaction: CELL-MEDIATED HYPERSENSITIVITY:activated T cells mediate reactions after 1-14 days delay


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Type I:Type I:Imm

ediat

eHyp

erse

nsitivityImm

ediat

eHyp

erse

nsitivity

mediators: histamine, enzymes, leukotrienes, ECF, NCF,

PAF, prostaglandins

effects: smooth muscle contraction; vasodilatation;vascular permeability; proteolytic destruction

examples:ANAPHYLAXIS; ALLERGICRHINITIS;

ATOPIC DERMATITIS


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AnaphylaxisAnaphylaxis


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Type II:Type II:AntibodyAntibody--mediatedCytotoxicitymediatedCytotoxicity

Complement-mediated CYTOTOXICITY: classic pathway

initiated by binding of Ag with eitherIgG orIgM formation

of the membrane attack complex Cytolysis

Antibody-Dependent Cell-mediated CYTOTOXICITY(ADCC): Antibody-coated target cells are lysed by killer (K)

cells

examples:AUTOIMMUNE HEMOLYTIC ANEMIA (AHA);

TRANSFUSIONREACTIONS; GOODPASTURES

SYNDROME; Rh INCOMPATIBILITY & HEMOLYTIC

DISEASE of the NEWBORN


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Autoimmune hemolytic anemiaAutoimmune hemolytic anemia


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Type III:Type III:ImmuneComplex DiseaseImmuneComplex Disease

Antigens: exogenous drugs, hormones,

infectious agents; autogenous/endogenous

altered DNA, tumors,abnormal proteins (e.g. RAfactor)

mechanisms:

interaction with Complement

interaction with Plateletsexamples: SLE(prototype);

POLYMYOSITIS; ARTHUSRXN;SERUMSICKNESS; PSGN


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Type IV:Type IV:CellCell--mediatedHypersensitivitymediatedHypersensitivity

Delayed type Hypersensitivity:

Tuberculin type TB skin test (PPD) purifiedprotein derivative is injected subcutaneously

results are read after 24;Granulomatous persistent Ags within

macrophages

Cell-mediated Cytotoxicity: class IIMHC Ag

CD4+ cells

ORGAN TRANSPLANTREJECTION

NKcell Cytotoxicity: viral or tumor targets


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Tuberculin testTuberculin test


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Transplant rejectionTransplant rejection


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AutoimmunityAutoimmunity

Loss of tolerance to self antigens (Tolerance is the normalstatus of immunologic non-responsiveness)

Theories:

Recognition of previously sequestered/hidden antigensDiminution of suppressor T cell function Increase in helper T cell activityT cell independent polyclonal B cell activation by

complex AgsModification of self-Ags by drugs, microbesCross-reactivity between autologous Ag & microbial

agents


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AutoimmuneDisordersAutoimmuneDisorders

Systemic Lupus Erythematosus prototype

Sjogrens syndrome

Scleroderma

Polymyositis

Dermatomyositis

Mixed connective tissue disease

Bullous disease of the skin Graves disease (1 hyperthyroidism)


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SystemicLupus ErythematosusSystemicLupus Erythematosus

Etiology: genetic HLA-DR2, -DR3, -A1, -B8; C2 & C4deficiency; hormonal - ; environmental viruses, drugs,toxins; usually affects women of childbearing age

Pathology: Auto-Antibodies:ANTI-NUCLEAR ANTIBODIES(ANA), spec.Ab to double-stranded DNA immunecomplex formation lymphocyte dysfunction; skin, joints,KIDNEYS, serosae, heart, blood vessels, lung, spleen,LNs, liver

Cause of death: RENAL FAILURE/SEPSIS


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Lesions of SLELesions of SLE

Wire-loop lesions

Libman-Sacks endocarditis

Butterfly rash


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Scleroderma

Sjogrens syndrome

Bullous disease of skin


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