Diseases of IMMUNITY - India’s Premier Educational ... · “Innate” and “Adaptive”...
Transcript of Diseases of IMMUNITY - India’s Premier Educational ... · “Innate” and “Adaptive”...
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Diseases of IMMUNITY
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OBJECTIVES• Differentiate between the concepts of
“Innate” and “Adaptive” immunity• Visually recognize and understand the basic
roles of lymphocytes, macrophages, dendritic cells, NK cells
• Understand the roles of the major cytokines in immunity
• Differentiate and give examples of the four (4) different types of hypersensitivity reactions
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OBJECTIVES• Know the common features of autoimmune
diseases, and the usual four (4) main features (Etiology, Pathogenesis, Morphology, and Clinical Expression) of Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjögrens, Systemic Sclerosis (Scleroderma), Mixed Connective Tissue Disease, and “Poly-” (aka, “Peri-”) -arteritis Nodosa
• Differentiate between Primary (Genetic) and Secondary (Acquired) Immunodeficiencies
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OBJECTIVES• Understand the usual four (4) main features
of AIDS, i.e., etiology, pathogenesis, morphology, clinical expression
• Understand the usual four (4) main features of Amyloidosis
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• INNATE (present before birth, “NATURAL”)
•ADAPTIVE (developed by exposure to pathogens, or in a broader sense, antigens)
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MHCMajor Histocompatibility Complex
• A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility
• Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice
• It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated
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INNATE IMMUNITY• BARRIERS• CELLS: LYMPHOCYTES,
MACROPHAGES, PLASMA CELLS, NK CELLS
• CYTOKINES/CHEMOKINES• PLASMA PROTEINS:
Complement, Coagulation Factors• Toll-Like Receptors, TLR’s
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ADAPTIVE IMMUNITY
•CELLULAR, i.e., direct cellular reactions to antigens
•HUMORAL, i.e., antibodies
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CELLS of the IMMUNE SYSTEM• LYMPHOCYTES, T - CD4 (helper), CD8
(cytotoxic)• LYMPHOCYTES, B• PLASMA CELLS (MODIFIED B CELLS)• MACROPHAGES, aka “HISTIOCYTES”,
(APCs, i.e., Antigen Presenting Cells)• “DENDRITIC” CELLS (APCs, i.e., Antigen
Presenting Cells)• NK (NATURAL KILLER) CELLS
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L
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P
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ANY ROUND CELL WITH RATHER DENSE STAINING CYTOPLASM AND MINIMAL CYTOPLASM IN CONNECTIVE TISSUE, A BIT BIGGER THAN AN RBC, IS A
LYMPHOCYTE…UNTIL PROVEN OTHERWISE
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MACROPHAGE
aka
HISTIOCYTE
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MACROPHAGES are MONOCYTES that have come out of circulation and have gone into tissue
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MACROPHAGES, TEM, SEM
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ANY CELL MIXED IN WITH LYMPHOCYTES BUT HAS A LARGER MORE “OPEN”, LESS DENSE, LESS CIRCULAR NUCLEUS WITH MORE CYTOPLASM IS A
MACROPHAGE…UNTIL PROVEN OTHERWISE
ALMOST ALL “GRANULAR” or “PIGMENTED” CELLS IN CONNECTIVE TISSUE ARE MACROPHAGES. GRANULOMAS, GIANT CELLS, ARE CHIEFLY MACROPHAGES ALSO.
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1) ROUND NUCLEUS
2) OVOID CYTOPLASM
3) PERIPHERAL CHROMATIN
4) “CLEAR ZONE” BETWEEN NUCLEUS AND WIDER LIP OF CYTOPLASM
PLASMA CELLS
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GENERAL SCHEME ofCELLULAR EVENTS
• APCs (Macrophages, Dendritic Cells)
• T-Cells (Control Everything)–CD4 “REGULATORS” (Helper)–CD8 “EFFECTORS”
• B-Cells Plasma Cells AB’s• NK Cells
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CYTOKINES• MEDIATE INNATE (NATURAL)
IMMUNITY, IL-1, TNF, INTERFERONS• REGULATE LYMPHOCYTE GROWTH
(many interleukins, ILs)• ACTIVATE INFLAMMATORY CELLS
• STIMULATE HEMATOPOESIS, (CSFs, or Colony Stimulating Factors)
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CYTOKINES/CHEMOKINES• CYTOKINES are PROTEINS produced by
MANY cells, but usually LYMPHOCYTES and MACROPHAGES, numerous roles in acute and chronic inflammation, AND immunity
–TNF, IL-1, by macrophages
• CHEMOKINES are small proteins which are attractants for PMNs
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MHCMajor Histocompatibility Complex
• A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility
• Also called HLA (Human Leukocyte Antigens) in humans and H-2 in mice
• It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized cells will NOT be tolerated
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MHC MOLECULES (Gene Products)
• I (All nucleated cells and platelets), cell surface glycoproteins, ANTIGENS
• II (APC’s, i.e., macs and dendritics, lymphs), cell surface glycoproteins, ANTIGENS
• III Complement System Proteins
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IMMUNE SYSTEM DISORDERSWHAT CAN GO WRONG?
• HYPERSENSITIVITY REACTIONS, I-IV• “AUTO”-IMMUNE DISEASES, aka
“COLLAGEN” DISEASES (BAD TERM)
• IMMUNE DEFICIENCY SYNDROMES, IDS:– PRIMARY (GENETIC)
– SECONDARY (ACQUIRED)
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HYPERSENSITIVITYREACTIONS (4)
• I (Immediate Hypersensitivity)• II (Antibody Mediated
Hypersensitivity)• III (Immune-Complex Mediated
Hypersensitivity)• IV (Cell-Mediated Hypersensitivity)
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Type I IMMEDIATE HYPERSENSITIVITY
• “Immediate” means seconds to minutes• “Immediate Allergic Reactions”, which may
lead to anaphylaxis, shock, edema, dyspnea death– 1) Allergen exposure– 2) IMMEDIATE phase: MAST cell
DEgranulation, vasodilatation, vascular leakage, smooth muscle spasm
– 3) LATE phase (hours, days): Eosinophils, PMNs, T-Cells
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TYPE II HYPERSENSITIVITYANTIBODY MEDIATED IMMUNITY• ABs attach to cell surfaces
– OPSONIZATION (basting the turkey)– PHAGOCYTOSIS– COMPLEMENT FIXATION (cascade of
C1q, C1r, C1s, C2, C3, C4, C5….. )– LYSIS (destruction of cells by
rupturing or breaking of the cell membrane)
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TYPE II DISEASES• Autoimmune Hemolytic Anemia, AHA• Idiopathic Thrombocytopenic Purpura,
ITP• Goodpasture Syndrome (Nephritis and
Lung hemorrhage)• Rheumatic Fever• Myasthenia Gravis• Graves Disease• Pernicious Anemia, PA
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TYPE III HYPERSENSITIVITYIMMUNE COMPLEX MEDIATED
• Antigen/Antibody “Complexes”• Where do they go?
– Kidney (Glomerular Basement Membrane)– Blood Vessels– Skin– Joints
• Common Type III Diseases- SLE (Lupus), Poly(Peri)arteritis Nodosa, Poststreptococcal Glomerulonephritis, Arthus reaction (hrs), Serum sickness (days)
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TYPE IV HYPERSENSITIVITYCELL-MEDIATED (T-CELL)
DELAYED HYPERSENSITIVITY• Tuberculin Skin Reaction
• DIRECT ANTIGEN CELL CONTACT– GRANULOMA FORMATION– CONTACT DERMATITIS
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SUMMARY• I Acute allergic reaction
• II Antibodies directed against cell surfaces
• III Immune complexes
• IV Delayed Hypersensitivity, e.g., Tb skin test
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RENALTRANSPLANT REJECTION• HYPERACUTE (minutes) : AG/AB
reaction of vascular endothelium
• ACUTE (days months): cellular (INTERSTITIAL infiltrate) and humoral (VASCULITIS)
• CHRONIC (months): slow vascular fibrosis
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ACUTE CELLULAR (T) ACUTE HUMORAL
CHRONIC
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AUTO-IMMUNE DISEASES• Failure of SELF RECOGNITION• Failure of SELF TOLERANCE• TOLERANCE
–CENTRAL (Death of self reactive lymphocytes)
–PERIPHERAL (anergy, suppression by T-cells, deletion by apoptosis, sequestration (Ag masking))
• STRONG GENETIC PREDISPOSITION• OFTEN RELATED TO OTHER AUTOIMMUNE
DISEASES• OFTEN TRIGGERED BY INFECTIONS
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CLASSIC AUTOIMMUNE DISEASES (SYSTEMIC)
•LUPUS (SLE) Systemic Lupus Erythematosus
• RHEUMATOID ARTHRITIS• SJÖGREN SYNDROME• SYSTEMIC SCLEROSIS (scleroderma)• “collagen” diseases (term no longer
used)
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CLASSIC AUTOIMMUNE DISEASES (LOCAL)
• HASHIMOTO THYROIDITIS• AUTOIMMUNE HEMOLYTIC ANEMIA• MULTIPLE SCLEROSIS• AUTOIMMUNE ORCHITIS• GOODPASTURE SYNDROME• AUTOIMMUNE THROMBOCYTOPENIA• “PERNICIOUS” ANEMIA• INSULIN DEPENDENT DIABETES MELLITUS• MYASTHENIA GRAVIS• GRAVES DISEASE
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• The list of diseases proven to be “autoimmune” grows by leaps and bounds every year!!!
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LUPUS (SLE)• Etiology: Antibodies (ABs) directed against
the patient’s own DNA, HISTONES, NON-histone RNA, and NUCLEOLUS
• Pathogenesis: Progressive DEPOSITION and INFLAMMATION to immune deposits, in skin, joints, kidneys, vessels, heart, CNS
• Morphology: “Butterfly” rash, skin deposits, glomerolunephritis (NOT discoid)
• Clinical expression: Progressive renal and vascular disease, POSITIVE A.N.A.
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H
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SLE, SKIN SLE, GLOMERULUS
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TABLE 6-10 -- Clinical and Pathologic Manifestations of Systemic Lupus Erythematosus
Clinical Manifestation
Prevalence
in Patients, %
Hematologic 100Arthritis 90Skin 85Fever 83Fatigue 81Weight loss 63Renal 50Central nervous system 50Pleuritis 46Myalgia 33Pericarditis 25Gastrointestinal 21Raynaud phenomenon 20Ocular 15Peripheral neuropathy 14
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MORE SYSTEMIC AUTOIMMUNE
DISEASES• RHEUMATOID ARTHRITIS• SJÖGREN SYNDROME• SCLERODERMA (SYSTEMIC
SCLEROSIS)
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NORMAL Bi-Layered Synovium
↑Destructive
Rheumatoid Synovitis
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SJÖGREN SYNDROME
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SCLERODERMA
(SYSTEMIC SCLEROSIS)
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SYSTEMIC SCLEROSIS
(SCLERODERMA)
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MORE AUTOIMMUNE DISEASES (LOCAL)
• HASHIMOTO THYROIDITIS• AUTOIMMUNE HEMOLYTIC ANEMIA• MULTIPLE SCLEROSIS• AUTOIMMUNE ORCHITIS• GOODPASTURE SYNDROME• AUTOIMMUNE THROMBOCYTOPENIA (ITP)• “PERNICIOUS” ANEMIA• INSULIN DEPENDENT DIABETES MELLITUS (I)• MYASTHENIA GRAVIS• GRAVES DISEASE
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IMMUNODEFICIENCIES•PRIMARY (GENETIC)
•SECONDARY (ACQUIRED)
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PRIMARY• CHILDREN with repeated, often severe
infections, cellular AND/OR humoral immunity problems, autoimmune defects
• BRUTON (X-linked agammaglobulinemia)• COMMON VARIABLE• IgA deficiency• Hyper IgM• DI GEORGE (THYMIC HYPOPLASIA) 22q11.2• SCID (Severe Combined Immuno Deficiency)• ….with thrombocytopenia and eczema
(WISKOTT-ALDRICH)• COMPLEMENT DEFICIENCIES
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ADA=
ADENOSINE
DEAMINASE
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Examples of Infections in Immunodeficiencies
Pathogen Type T-Cell-Defect B-Cell DefectGranulocyte
Defect Complement DefectBacteria Bacterial sepsis Streptococci,
staphylococci, Haemophilus
Staphylococci, Pseudomonas
Neisserialinfections, other pyogenic bacterial infections
Viruses Cytomegalovirus, Epstein-Barr virus, severe varicella, chronic infections with respiratory and intestinal viruses
Enteroviral encephalitis
Fungi and parasites
Candida, Pneumocystis carinii
Severe intestinal giardiasis
Candida, Nocardia, Aspergillus
Special features Aggressive disease with opportunistic pathogens, failure to clear infections
Recurrent sinopulmonary infections, sepsis, chronic meningitis
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(SECONDARY IDS)• Etiology: HIV• Pathogenesis: Infection, Latency,
Progressive T-Cell loss• Morphology:
• Clinical Expressions: Infections, Neoplasms, Progressive Immune Failure, Death, HIV+, HIV-RNA (Viral Load)
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EPIDEMIOLOGY• HOMOSEXUAL (40%, and
declining)• INTRAVENOUS DRUG
USAGE (25%)• HETEROSEXUAL SEX (10%
and rising)
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ETIOLOGY
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PATHOGENESIS
ATTACHING BUDDING
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PATHOGENESIS
EARLY BUDDING
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PATHOGENESIS
LATE BUDDING
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PATHOGENESIS
MATURE NEW VIRIONS
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REVERSE TRANSCRIPTASE• The enzyme reverse transcriptase
(RT) is used by retroviruses to transcribe their single-stranded RNA genome into single-stranded DNA and to subsequently construct a complementary strand of DNA, providing a DNA double helix capable of integration into host cell chromosomes.
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PATHOGENESIS
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PATHOGENESIS
1) PRIMARY INFECTION
2) LYMPHOID INFECTION
3) ACUTE SYNDROME
4) IMMUNE RESPONSE
5) LATENCY
6) AIDS
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GENERAL IMMUNE ABNORMALITIES
• LYMPHOPENIA• DECREASED T-CELL
FUNCTION• B-CELL ACTIVATION,
POLYCLONAL• ALTERED
MONOCYTE/MACROPHAGE FUNCTION
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INFECTIONS• Protozoal/Helminthic:
Cryptosporidium, PCP(Pneumocystis Carinii Pneumonia), Toxoplasmosis
• Fungal: Candida, and the usual 3• Bacterial: TB, Nocardia,
Salmonella• Viral: CMV, HSV, VZ
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CRYPTOSPORIDIUM
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CASEATING GRANULOMA
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CANCERS of AIDS• KAPOSI SARCOMA• B-CELL LYMPHOMAS• CNS LYMPHOMAS• CERVIX CANCER,
SQUAMOUS CELL
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AMYLOIDOSIS• BUILDUP OF AMYLOID “PROTEIN”
– AL (Amyloid Light Chain)– AA (NON-immunoglobulin protein)– Aß (Alzheimer’s)
• WHERE? BLOOD VESSEL WALLS, at first– KIDNEY– SPLEEN– LIVER– HEART
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CONGO RED STAIN, WITHOUT, and WITH, POLARIZATION
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AMYLOID ASSOCIATIONS• PLASMA CELL “DYSCRASIAS”, i.e.,
MULTIPLE MYELOMA• CHRONIC GRANULOMATOUS
DISEASE, e.g., TB• HEMODIALYSIS• HEREDOFAMILIAL• LOCALIZED• ENDOCRINE MEAs (Multiple Endocrine
Adenomas)• AGING