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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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cells of the immune response:cells of the immune response:
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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cells of the immune response:cells of the immune response:
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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cells of the immune response:cells of the immune response:
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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cells of the immune response:cells of the immune response:
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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cells of the immune response:cells of the immune response:
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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cells of the immune response:cells of the immune response:
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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HistocompatibilityAntigensHistocompatibilityAntigens
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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HistocompatibilityAntigensHistocompatibilityAntigens
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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HistocompatibilityAntigensHistocompatibilityAntigens
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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Thank You !Thank You !
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