Post on 23-Jun-2020
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Immunopathology Part II
Autoimmune Disease
Pathology of Transplantation
Laboratory evaluation of the Immune System
Immunodeficiency
Amyloidosis
Immune Mediated Tissue Injury
ANTIGEN
B-CELLS T-CELLS
APC
CD4 CD8
DELAYED-TYPE HYPERSENSITIVITY
CYTOTOXICITY
ANTIBODIESand IMMUNECOMPLEXES
IgE andALLERGICDISEASE
IVII, III
I
+
+
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Autoimmunity andAutoimmune Disease
Autoimmune Disease: Single-Organ And Systemic (Multiorgan)
Organ-Specific Systemic
Hashimoto thyroiditis Systemic Lupus ErythematosusAutoimmune hemolytic anemia Rheumatoid ArthritisMultiple Sclerosis Sjogren SyndromeAutoimmune Orchitis Reiter SyndromeGoodpasture Syndrome Inflammatory MyopathiesAutoimmune Thrombocytopenia Systemic SclerosisInsulin Dependent Diabetes MellitusMyasthenia GravisGraves DiseaseAutoimmune Hepatitis
Mechanisms of Autoimmunity Antinuclear Antibody IF
Homogeneous
Peripheral/rim
Speckled
Centromere
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Antinuclear Antibody IF
Anti dsDNA: Crithidia lucida
Extractable Nuclear Antigens:“Alphabet Soup”
Anti ds-DNA (native DNA): 40-60% SLE (< 5% other)Anti-histone: 50-70% SLE (< 5% other)Anti-Smith (Sm): 20-30% SLERNP (ribonucleoprotein):
SS-A (Ro): 70-95% SS, 30-50% SLESS-B (La): 60-90% SS, 10-15% SLE
Scl-70 (DNA topoisomerase I): 28-70% PSS10-18% limited Scl.
Anti centromere: 90% limited Scl., 22-36% PSS
Anti-Jo-1 (Histidyl tRNA synthetase): 25% myositis
Autoantibodies: LE Cell
Systemic Lupus Erythematosus
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Systemic Lupus ErythematosusA systemic autoimmune disease
Incidence: 1/2500 (40/100,000) N. European
SKIN
KIDNEY
BLOOD CELLS
CNS
LUNGS,OTHER
Immune-mediatedInflammation
JOINTSCARDIO-VASCULAR
“GarbageDisposal
Hypothesis”
AUTOANTIBODIES IN SLE
Antinuclear antibodies:
ANA ScreenAnti-dsDNAAnti-Sm
Antiphospholipid AntibodiesAntigens: beta-2 glycoprotein, annexin
Other Autoantibodies
Pathology of SLE: Kidney
Class I Normal (LM)
Class II Mesangial
Class III Focal Proliferative
Class IV Diffuse Proliferative
Class V Membranous
Pathology of SLE: Kidney
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Pathology of SLE: Kidney Pathology of SLE: Kidney
Pathology of SLE: Kidney EM Systemic Lupus ErythematosusSkin Involvement
Pathology of SLE: Skin Pathology of SLE: Skin
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Pathology ofSLE:
Heart
Libman SachsEndocarditis
Accelerated Atherosclerosis
Pathology of SLE: Spleen
1-3: SKIN: malar rash 85%discoid rashphotosensitivity
4-6: SURFACE INFLAMMATION: oral ulcers arthritisserositis 25-45%
7: RENAL: proteinuria 50-70%casts
8: NEUROLOGICAL: seizures 25-30%psychosis
9: HEMATOLOGIC: cytopenias100%
10: IMMUNOLOGIC: anti dsDNA, Antiphospholipid, anti Sm
11: ANA
SLE REVISED CRITERIA
Systemic Lupus Erythematosus
Natural History and Prognosis:
Unpredictable course with episodic exacerbations (flares)
Patterns of autoantibody expression:
Survival1950s 4 yr survival 50%Current 15 year survival 80%
Mortality: Bi-phasic
Early: severe inflammatory disease (lupus), or infectionLate: myocardial infarction, stroke
Systemic Lupus Erythematosus:
Treatment
Minor symptoms: NSAIDSlow dose prednisone
Moderate to Severe HydroxychloroquineCorticosteroidsmycophenolate mophetilAzathioprineAnti B-cell agents: Rituximab
**Also: Aggressive modification of cardiacrisk factors
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Discoid LupusLupus Variants
Drug Induced “Lupus”
Drugs: hydralazine, procainamide, isoniazid,penicillamine
+ ANA may be only feature(anti-histone >95%)
+/- Skin and Multisystem involvement
CNS involvement rare
Sjogren Syndrome
Sicca syndrome
Mikulicz disease
Sjogren Syndrome: Salivary Gland
Sjogren Syndrome: Lymphoepitheliallesion
Sjogren Syndrome; Chronic inflammationand Atrophy
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Sjogren Syndrome: Complications: Malignant Lymphoma Scleroderma
(Progressive Systemic Sclerosis)
Diffuse Cutaneous
Localized Cutaneous
Limited: CREST
Nailbed Capillaroscopy
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Raynaud’s Phenomenon
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Progressive Systemic Sclerosis
Clinical features:
Raynaud’s phenomenonSkin changesMusculoskeletalGIPulmonaryCardiacRenal
Autoimmune Inflammatory Myopathies
Dermatomyositis
Heliotrope skin rash + myopathy (proximal to distal)
Children and adults affected
Extra muscular disease: lung
Capillaries are major target
Dermatomyositis
Polymyositis
Myopathy without skin involvement
Predominantly adult disease
Direct cell mediated infiltration of muscle
Systemic involvement: heart, lungs
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Polymyositis
Immunopathology
Pathology of Transplantation
Transplant Rejection
Increasing Graft Survival
Graft versus Host Disease
Other Complications
December 23, 1954: First Successful Kidney Transplant Boston Mass.
Mechanisms Of RejectionClassification of Rejection
Hyperacute: minutes-hoursAcute: days to years
acute cellular rejectionacute vascular rejection
Subacute: months
Chronic: years
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HyperacuteRejection
Acute Rejection
Acute VascularRejection
Chronic Rejection
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Chronic RejectionAcute Rejection, Heart
Bile Duct
Acute Rejection: Liver
Increasing Graft Survival
ABO Blood Group MatchingMHC/HLA Antigen MatchingOld: microlymphocytotoxicity
mixed lymphocyte cultureantibody screening
Current: HLA typing: DNA-based (PCR)Crossmatching by flow cytometry
Immunosuppression
Immunosuppressive Drugs
Drug Year Mechanism
Corticosteroids 1960 blockade of cytokine gene transcription lymphs, macrophages/APCs
Azathioprine 1962 blockade purine synthesisin myeloidcells
Cyclosporine 1980 inhibition of IL2 synthvia calcineurin pathwayblockade
OKT3 1980 binds to CD3 complex
Immunosuppressive Drugs
Drug Year Mechanism
Mycophenolate early90s blockade of purine Mofeteil synthesis (lymphocytes)
Tacrolimus late 90s calcineurin blockade(FK506)
Sirolimus late 90s inhibition of IL2 signal transduction
Anti-IL2 late90s binds to alpha subunitreceptor of IL-2receptor
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NEJM Vol 351:26 December 2004
Renal Allograft Survival 1988-1996
Living Related Donor Cadaveric
NEJM Vol 342 March 2000
NEJM Vol 346, No 8 2002
Graft vs Host Disease
GVHD: Skin
AcuteGVHD
Skin involvement
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GVHD: Skin
Acute GVHD: Colon
GVHD: Liver
Post-TransplantLymphoproliferativeDisorder
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Immunodeficiency DiseasesCongenital and Acquired
Assessing the Status of theImmune System
Assessing the Status of the ImmuneSystemSerum Protein Electrophoresis
Hypogammaglobulinemia
Flow Cytometry
Lymphocyte subsets
Tcell proliferation
Hyper IgM syndrome (CD40L)
Leukocyte adhesion deficiency
Cytokine expression
PNH (complement regulatoryProteins CD55, CD59)
Immunophenotyping ofleukemia, lymphoma
HLA typing
Stem cell enumeration
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CD4 LymphocyteQuantitation byFlow Cytometry
Assessing the Status of the Immune System
Lymphocyte Activation Testing
Unstimulated lymphocytes Stimulated lymphocytes
Assessing the Status of the ImmuneSystem
Skin Testing
Tuberculin Candida
Nitroblue Tetrazolium Test
CATEGORIES OF IMMUNODEFICIENCY DISORDERS
Antibody deficiencies and defects 65%
Combined antibody and cellular deficiencies 15%
Disorders of phagocytes 10%
Isolated cellular defects 5%
Complement deficiencies/disorders 5%
Other disorders of innate immunity <1%
Lymphocyte Development and Immunodeficiency
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X-Linked (Bruton’s) Agammaglobulinemia Other Humoral Immunodeficiencies
Severe Combined Immunodeficiency
Buckley, R. H. N Engl J Med 2000;343:1313-1324
Relative Frequencies of the Various Types of Severe Combined Immunodeficiency among 141 Consecutive Patients
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Gene Therapy
RetroviralVector
γc cytokinereceptor
gene
Wiskott-Aldrich Syndrome
Triad:EczemaThrombocytopenia with small plateletsRecurrent Infections
Complement Deficiencies
Early components: C1q, C2, C4C1q EsteraseC5-9
Phagocyte Deficiencies
Chronic GranulomatousDisease (CGD)NADPH oxidase deficiency
Pathology and Pathogenesisof HIV Infection
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HIV INFECTION
Mode of Transmission and Spread
Sexual Transmission (75%)
FLUIDSEFFICIENCY OF TRANSMISSIONMODIFYING FACTORS
Parenteral
IV DRUG USETRANSFUSION
1 in 2 million units transfusedNEEDLE STICK less than 1 in 300
PerinatalINTRAUTERINE/TRANSPLACENTALINTRAPARTUMBREAST FEEDING
HIV GENOME
HIVCELL BINDING AND ENTRY
CXCR4 and CCR-5 T CELLSCCR-5 only MACROPHAGEChemokine receptors:
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HIVIntracellular life cycle
HIV
Overview ofPathogenesis
HIVMechanisms of T-cell Loss
HIVEffects of loss of Helper T cells
Natural History of HIV Infection
“set point”
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HIV INFECTIONClinical Phases:A)Acute HIV, generalized lymphadenopathyB) Symptomatic (not A or C)C) AIDS indicator conditions
T Cell (CD4) Stages:I) > 500/uLII) 200-499/uLIII) < 200/uL
Clinical and PathologicFeatures of AIDS
Acute HIV Infection
Kahn, J. O. et. al. N Engl J Med 1998;339:33-39
HIVLymphadenopathy
Primary CNSLymphoma
Kaposi’sSarcoma
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Kaposi’s Sarcoma Kaposi’s Sarcoma
Pathogenesis of Kaposi’s Sarcoma
Cervical Cancer and HPV
HIV-Associated CNS Disease
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Progressive Multifocal LeukoencephalopathyMycobacterial Disease in AIDS
M. tuberculosisM. Avium complex
M. Avium in spleen AFB stain
PneumocystisJeroveci
H&E GMS
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HistoplasmosisCryptococcusneoformans
Toxoplasmosis
Cryptosporidium
Cytomegalovirus
Jacobson, M. A. N Engl J Med 1997;337:105-114
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HIV SCREENING
ELISA (HIV 1 and 2)
POSITIVE (repeatedly)
WESTERN BLOT
POSITIVEHIV 1INFECTION
NEGATIVE
HIV 2 TESTING
INDETERMINANT
HIV 1 AbIF
HIV-1 ProviralDNA by PCR
POSITIVEHIV 1INFECTION
NEGATIVE
POSITIVEHIV 1INFECTION
NEGATIVE
REPEAT ELISA 1-3 MOS—Hi Risk
NEGATIVE
HIV: Targets for anti-retroviral therapy
Clavel, F. et. al. N Engl J Med 2004;350:1023-1035
Complex of HIV-1 Reverse Transcriptase with an RNA-DNA Duplex
Slide 7.45
Amyloidosis
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Pathogenesis of Amyloidosis
Slide 7.46
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Slide 7.47
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Localized Amyloidosis: Pancreas