Transcript COMPLEMENT

Here is what Step 1 covers- did
we get them all?
• Production/function granulocyte, NK cells and macrophages/DC
• Production/function of T cells, TCR, cytokines/chemokines
• Production/function of B cells and PC, Ig structure, classes, molecular
basis for specificity, receptors
• Antigenicity/immunogenicity, host defenses(read Innate I),
primary/secondary responses, passive transfer of immunity(all ways)
• In vitro complement, other diagnostic tests and antigen antibody
reactions
• Mediators, complement, aa, histamine, NO and cytokines
• MHC structure and function, RBC antigens. Transplantation
• Vaccines, protective immunity, tumor immunity
• Disease states like ID, HIV and pharmacological immunosuppression
INNATE IMMUNITY
• NOT ANTIGEN SPECIFIC
• HAS NO MEMORY
• MEDIATED BY
– NEUTROPHILS
– MACROPHAGES/MONOCYTES
– NATURAL KILLER CELLS
– EOSINOPHILS
– BASOPHILS/MAST CELLS
– MANNOSE BINDING PROTEIN AND COMPLEMENT
– PROSTAGLANDIN & KININ SYSTEMS
INDISCRIMINATE DESTRUCTION
PRO-INFLAMMATORY CYTOKINES
ADAPTIVE IMMUNITY
• ANTIGEN SPECIFIC
• CLONAL EXPANSION
• AMPLIFIES AN IMMUNE RESPONSE AFTER A
SPECIFIC RECEPTOR INTERACTION
• INTEGRATES THE INNATE RESPONSE INTO THE
REACTION
• MEMORY OF THE ENCOUNTER
KNOW THESE DIFFERENCES
ANATOMY OF THE IMMUNE
SYSTEM
B-CELL DEVELOPMENT
ANTIBODY STRUCTURE
ANTIBODY FUNCTIONS
ANTIBODY FUNCTIONS
COMPLEMENT
• FLUID PHASE AMPLIFIER OF
INNATE AND ANTIBODY MEDIATED
RESPONSES
• THREE ARMS
– ALTERNATE-BACTERIAL CELL WALLS
– MANNOSE BINDING-BACTERIAL CELL
WALLS and MBP
– DIRECT(CLASSIC)-SPECIFIC Ag/Ab
REACTIONS
COMPLEMENT
COMPLEMENT
• ENZYME ACTIVATED CASCADE WITH
GENERATION OF INFLAMMATORY AND
REGULATORY FRAGMENTS
• ACTIVATES INFLAMMATORY CELLS BY SPECIFIC
RECEPTOR INTERACTIONS
• HAS IMPORTANT IMMUNOREGULATORY AND
IMMUNE COMPLEX DISPOSAL ROLES
• Measured by serum C3 and C4, total hemolysis and
individual components
COMPLEMENT-RELATED DISEASES
• Rare
• C1esterase deficiency with angioneurotic
edema• Deficiencies in the direct sequence associated
with IC diseases like SLE
• Homozygous C3 is lethal
• Deficiencies in the alternate path very rare
• Individual component deficiency after C5
associated with Neisserial bacteremia
ANTIGEN PRESENTING CELLS
MHC
T-CELL DEVELOPMENT
T-CELL FUNCTIONS
QUESTIONS
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From stem cell to T cell
why the thymus
CD4 versus CD8
gamma delts versus alpha bets
peripheral blood
CDs to remember……….
– 3,4,8,25,19,16,20,
MORE CYTOKINES TO
REMEMBER
Il-12, INF- and IL-2 =TH1 response
IL-4 =TH2 response & antibody formation
IL-10, IL- 4 = suppression of Th1
INF- = suppression of TH2
IL-8 = neutrophils
IL-5= eosinophils
TGF- = healing
IL-6 = fever and cachexia
TNF- =inflammation (RA),sepsis and SIRS,
monoclonals available to inhibit some syndromes
MHC
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Co-dominant alleles
Present on Chromosome 6 in humans
A,B,C loci are Class I
D loci are class II and control immune
responses and rejection
MLC
TRANSPLANT TYPES
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Autograft
Isograft
Allograft (also known as Homograft)
Xenograft
TRANSPLANT REJECTION
HERESY
CLASSIC
1L-4
IL-4
DONOR
DC
3
IL-4
Th1 Th1
4
IL-4
B
CD8
3
B
IL-2
Th2
HO ST
DC
5
B
CD8
B
Th2
Th2
Th1 Th1
Th2
5
4
IL-2
CD8
CD8
INF-
INF-
1
2
NK
MAC
C’
DONOR ORGAN
6
1
2
MAC
NK
IMMUNOSUPPRESSION
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Corticosteroids-inhibit NFB
Cyclosporine-inhibit T-cell activation
Tacrolimus- inhibit T-cell activation
Rapamycin- block IL-2 receptor activation
Anti-cytokine/ligand monoclonals
PREDICT THE TYPE OF
INFECTION
• Pure B cell…encapsulated bacteria and systemic spread of
GI viruses..frequent after 6 mos of age
• “pure” T cell….TB, fungi, pneumocystis since helper
function is lost…occurs at birth. B cell infections will not
occur until maternal antibody gone-approx 6 mos
• B & T cell..at birth, severe and fatal if not transplanted
• CGD –neutrophil inability to kill bacterial that produce
catalase..esp staph
• cytokine..IL-12, Interferon gamma, IL-4
DISEASES ASSOCIATED WITH TCELL DEFICIENCY
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HIV/AIDS
THYMIC APLASIA
SENESCENCE
BIRTH
WISKOTT-ALDRICH
ATAXIA-TELANGIECTASIA
TREATMENT
DISEASES ASSOCIATED WITH BCELL DEFICIENCY
• X-LINKED
AGAMMAGLOBULINEMIA
• COMMON VARIABLE
IMMUNODEFICIENCY
• SELECTIVE IgA DEFICIENCY
• CLL
• HYPER IgM SYNDROME
• TREATMENT
DISEASES ASSOCIATED WITH T & B
CELL DEFICIENCY
• SCID
• THERAPY:
– STEM CELL TRANSPLANTS
– BMT
– GENE REPLACEMENT- recent problems with
the retroviral vector insertion has led to
leukemia
TESTING IMMUNE FUNCTION
• B-CELLS
– SERUM IG LEVELS
– ELECTROPHORECTIC DETECTION OF
CLONALITY
– ENUMERATION OF B-CELLS
– DETECTION OF SPECIFIC ANTIBODIES
– IMMUNOHISTOPATHOLOGIC
Know your Flow!
TESTING IMMUNE FUNCTION
• T-CELLS
– IN VIVO SKIN TESTING- will not be valid in
patients with malnutrition, on steroids etc
– ENUMERATION OF T-CELLS-can be
misleading because doesn’t reflect tissue
distribution
– IMMUNOHISTOPATHOLOGIC
– IN VITRO FUNCTIONS- rarely needed
HYPERSENSITIVITY REACTIONS
• TYPE I- Atopy, asthma & anaphylaxis
• TYPE II-Antibody to cell structuresimmune thrombocytopenia, AIHA
• TYPE III- Immune complex diseasesSLE is prototype
• TYPE IV- Delayed hypersensitivitysarcoidosis
AN ALLERGIC REACTION
EARLY
OR
ACUTE
VASOACT IVE MEDIATORS
IL-5
MAST
CELL
IL-4
IgE
EOS
ALLERGEN
B CELL
IL-4
Th2
DENDRITIC CELL
IL-5
MAST
CELL
LATE
ALLERGY MEDIATORS
ASTHMA
Asthma
• Limited early exposure to infections-socalled hygiene hypothesis
• Obesity
• Genes
– Maternal 11 for IgE increase
– T-bet gene abnormalitiesfor deficient INF-
– IL-13
AUTOIMMUNE DISEASES
AUTOIMMUNE DISEASES
IMMUNE COMPLEX
DISEASE-AKA SERUM
SICKNESS
AUTOANTOBODIES
• SLE– ANA is a SCREENING TEST ONLY(HIGH
SENSITIVITY, LOW SPECIFICITY)
– double stranded(ds/native) DNA correlates loosely with
renal disease, very specific
– Sm very specific for SLE-low sensitivity
– Histone- present in drug induced lupus but also SLE
and other diseases
– Ribonucleoprotein (RNP)- associated with mixed
connective tissue disease
AUTOANTOBODIES
– ANCA
• cANCA high specificity for Wegeners
Granulomatosus
• pANCA found in some glomerulonephritis,
microscopic vasculitis and other vasculitis
Polymyositis/Dermatomyositis……anti-JO-1
SS-A(Ro)/SS-B(La)- Sjogren syndrome, congenital
heart block
MORE AUTOANTIBODIES
• Scleroderma
– SCL-70( aka anti-topoisomerase) specific but
very low sensitivity
– Centromere-high sensitivity for CREST(limited
scleroderma) and codes for presence of
pulmonary hypertension
Other Autoantibodies to remember
• AntiAcR- myasthenia
• Anti-endomysial- Sprue (anti gliadin)
• Rheumatoid factor- not specific for RA
Acute Phase reactants
• C-reactive Protein•
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Most accurate indicator of an inflammatory reaction
Proxy for IL-6
May correlate independently of Lipids for CA
High likelihood something about CRP will be on
Boards!..especially as independent indicator of
coronary artery disease
Transferrin, ceruloplasmin, C3, haptoglobin
increase with infection, albumin and
hemoglobin decrease
HLA ASSOCIATIONS WITH SPECIFIC
DISEASES
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Ankylosing spondylitis-B27……………….90RR*
Reactive Arthropathy-B27.………………...40
Rheumatoid Arthritis-DR4.………………...4
Behcet’s-B51.………………………………4
SLE-DR3.…………………………………..6
IDDM-DR3,4……………………………….6
Dermatitis Herpetiformis-DR3.…………….16
MS-DR2…………………………………….4
Goodpastures-DR2…………………………16
Birdshot Retinochoroidopathy-A29.……….109**
– *…remember the caveats, ** …..for that extra point
TERMS TO REMEMBER
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ANTIGEN
IMMUNOGEN
EPITOPE
HAPTEN
ADJUVANT
STEM CELLS
PRIMARY AND SECONDARY IMMUNE
RESPONSE
TERMS TO REMEMBER
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INNATE(AKA NATURAL)
ADAPTIVE(SPECIFIC OR ACTIVE)
CELL-MEDIATED IMMUNITY
HUMORAL/ANTIBODY IMMUNITY
PASSIVE IMMUNIZATION
ACTIVE IMMUNIZATION
ARTHUS REACTION
TERMS TO REMEMBER
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ISOTYPE
IDIOTYPE
MONOCLONAL
SYNGENEIC
ALLOGRAFT
AUTOGRAFT
ELISA & RIA
Here is what Step 1 covers- did
we get them all?
• Production/function granulocyte, NK cells and macrophages/DC
• Production/function of T cells, TCR, cytokines/chemokines
• Production/function of B cells and PC, Ig structure, classes, molecular
basis for specificity, receptors
• Antigenicity/immunogenicity, host defenses(read Innate I),
primary/secondary responses, passive transfer of immunity(all ways)
• In vitro complement, other diagnostic tests and antigen antibody
reactions
• Mediators, complement, aa, histamine, NO and cytokines
• MHC structure and function, RBC antigens. Transplantation
• Vaccines, protective immunity, tumor immunity
• Disease states like ID, HIV and pharmacological immunosuppression
T-CELL FUNCTIONS
Isotype switching