Immunology- Micr360/860

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Jules Bordet

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discoverer of complement (1870-1961)
Nobel Prize 1919

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primary synthetic sources of complement

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*monocytes/macrophages
*hepatocytes

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Classical Complement Activation pathway

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activated by antigen-antibody complexes
C1complex-C4//C4b-C2//C4b2a=C3 convertase-C3//C4b2a3b=C5 convertase

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Alternative Complement Activation pathway

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activated on microbial surfaces in the absence of antibody
C3/spon/C3b-Factor B-FactorD//C3bBb=C3 convertase-C3//C3bBbC3b=C5 convertase

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Lectin Complement Activation pathway

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activated by serum mannose-binding lectin (MBL) binding to massose residues on glycoproteins or carbohydrates on surface of microbes in the absence of antibody
MBP-MASP-C4//C4b-C2//C4b2a=C3 convertase-C3//C4b2a3b=C5 convertase

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First Line of Defense

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Anatomic and Physiologic Barriers

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defensins

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cysteine-rich peptides, present in skin and abundant in neutrophil granules

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neutrophil granules contain:

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-defensins
-hypochlorous acid
-phagocyte oxidase
-iNOS

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inflammatory barrier

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first step in natrual/innate response
-vasodilation, increase in capillary permeability, influx of phagocytes
-erythema, edema, heat pain

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natural/innate immune response

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first wave of immune responses
1. inflammatory barrier
2. phagocytic barrier

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erythema

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redness

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margination

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leukocytes preparing to crawl through vessel wall

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extravasation

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leukocyte crawling through venule wall

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phagocytic barrier

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natural/innate response
-neutrolphils
-macrophages
-eosinophils

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neutrophils

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-early phagocytosis
-excellent killing (high respiratory burst)
-inflammation and tissue damage

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macrophages

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-efficient phagocytosis
-secretion of cytokines to stimulate inflammation and immune cells

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NK cells

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-natural killers
-non-phagocytic
-lysis of infected cells via Fas/FasL system
-activates macrophages

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TLR-1

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recognizes bacteria parasites

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TLR-2

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recognizes bacteria parasites, gram positive bacteria and fungi

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TLR-3

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recognizes dsRNA viruses

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TLR-4

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recognizes Gram-negative bacteria

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TLR-5

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recognizes flagellated bacteria

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TLR-6

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recognizes Gram-positive bacteria and fungi

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TLR-7

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recoginzes ssRNA viruses

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TLR-8

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recoginzes ssRNA viruses

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TLR-9

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recognizes bacteria dsDNA dinucleotides (viruses..)

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PAMPS

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pathogen-associated molecular patterns, which are recognized by TOLL-like receptors of innate immunity cells

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opsonization

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coating of a microbe in order for easier digestion by a phagocyte
-complement, antibodies (IgG1 and 3), CRP, collectin

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respiratory burst

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phagolysosome turns O2-->superoxide with phagocyte oxidase, Arginine-->NO with iNOS to kill microorganism

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phagocyte oxidase

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converts O2-->superoxides

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iNOS

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intracellular nitric oxide synthetase; converts Arginine-->NO

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complement

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30 different glycoprotein molecules
*innate protein
-kill microbes (C9 MAC attack)
-opsonize microbes
-activate leukocytes

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collectin

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mannose-binding lectin
*innate protein
-opsonizes MOs
-activates complement by binding with MASP-1 and 2

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pentraxin

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C-reactive protein
*innate protein
-acute phase protein, secreted by hepatocytes b/c of fever or damage mediators
-opsonizes
-activates complement (?)

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innate soluble proteins

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-complement, cytokines, CRP, collectin, lysozymes, coagulation factors

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cardinal features of adaptive immune response

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-specificity
-memory
-diersity
-specialization
-self-limitation
-discrimination

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reticulo-endothelial system (RES)

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aka mononuclear phagocyte system
-all areas of body with macrophages, I think

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Kupffer cells

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liver (MPS/RES)

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mesangial cells

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kidney (MPS/RES)

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primary lymphoid organs

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thymus and bone marrow
-where T and B cells develop

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secondary lymphoid tissue

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aka peripheral
tonsils and adenoids, lymph nodes, spleen, MALT, cutaneous tissues

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high endothelial venule (HEV)

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specialized blood vessel with no tigh junctions
-allows T and B cells to migrate into lymph node

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lymph node cortex

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contains follicles of B cells and germinal centres
also follicular dendritic cells

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lymph node paracortex

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contains T cells and interdigitating dendritic cells

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lymph node medulla

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contains medullary cords of B cells and plasma cells

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langerhans cells

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dendritic cells in the epidermis and mucousal membranes
-phagocytic/APC function

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interstitial dendritic cells

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dendritic cells that populate most organs
-phagocytic/APC function

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interdigitating dendritic cells

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dendritic cells found in T-cell areas of secondary lymphoid tissues and thymic medulla
-phagocytic/APC function

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veiled cells

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circulating dendritic cells found in blood and lymph
-phagocytic/APC function

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follicular dendritic cells

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dendritic cells found in B cell rich follicles
-don't function as APC, express lots of membrane receptors of antibody and complement, which bind to facilitate B-cell activation

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marginal zone

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in spleen, where B cells and dendritic cells are

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periarterial lymphatic sheath (PALS)

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in spleen, where T-cells are

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M cell

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microvilli cells
-anple antigens in lumen, bring them to B and T cells inside

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MALT

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mucous-associated lymphoid tissue
-biased toward IgA, have own specialized lymphocytes (mucosal homing receptors)

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granulocytes

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*contain inflammatory mediators in their granules
-neutrophils
-eosinophils
-basophils

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characteristic B-cell markers

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CR-1 and 2
B220 (CD45R)
B7
CD40

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CR-1

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-characteristic B-cell marker
-inhibits complement pathway

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B220/CD45R

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frequently used as a marker for B-cells
"leukocyte common antigen"

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B7

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important regulatory molecule

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CD40

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critical for survivial of antigen-stimulated B-cells

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B cells fight against...

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...extracellular phases of bacterial and viral infections, and toxins

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T cells fight against...

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fungal, parastice and intracellular viral and bacterial infections; tumour cells; transplated organs/tissues

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immunogen

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molecule that has the ability to evoke a specific immune response and can react with the resultant specific antibody

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factors that influence immunogenicity

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-foreignness
-molecular size > 10000Da
-molecular complexity
-degradability
-more particulate
-denatured

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isogeneic/autologous

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of own self

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syngeneic

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from same genes

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allogeneic

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from different individual of same species

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xenogeneic

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from different species

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adjuvants

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when mixed with antigen and injected, enhances the immunogenicity of that antigen only

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aluminum potassium sulfate (alum)

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used in vaccines with Bordetella pertussis

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dinitrophenol (DNP)

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the hapten with BSA

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bovine serum albumin (BSA)

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the carrier protein for DNP

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factors affecting cross-reactivity

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inhibiting:
-strong acidic groups
-glycoside groups
enhancing:
-nonionic radical groups

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heteroclitic antibodies

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higher affinity for cross-reacting epitopes than for their homologous epitope

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multiple myeloma

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monoclosal tumours of antibody-producing plasma cells
-also secrete Bence-Jones proteins

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hybridomas

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mutant myeloma cell line crossed with activated spleen cells from a mouse
-able to grow in HAT medium

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ADCC

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antibody-dependent cell-mediated cytotoxicity
-carried out by T-cells and NK cells

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functions of immunoglobulins

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*antigen binding
-fixation of complement
-->lysis of cells, clearance of immune complexes
-binds phagocytic cells, T-cells, NK cells, mast cells and basophils

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hinge region

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region at which the arms of teh Ab form a Y
-some flexibility here except in IgM and IgE

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oligosaccharides

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carbs N-linked to the C(H2) domain in most immunoglobulins

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immunoglobulin superfamily

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Ig, TCR, CD4, CD8, CD3, MHC class I and II

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HVR/CDR

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hypervariable/complementary determining regions

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frameword regions

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areas outside of HVR/CDRs in binding cleft of Ig

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papain

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cleaves Ig into 2Fab + Fc

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pepsin

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enzymes that cleaves Ig into F(ab)2

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IgG

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gamma heavy chains
-80% in serum
-activates complement
-opsonization
-crosses placenta

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IgA

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alpha heavy chains
-Jchain and secretory component
-in secretions, incl milk
-doesn't activate complement or cross placenta
-monomeric in serum, dimeric in secretions
-T or Y form

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IgM

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mu heavy chains
-pentamer with J chain
-B cell surface receptor
-maj of first immune response
-four heavy domains, no hinge region
-good agglutinator
-natural antibodies
-activates complement

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IgD

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delta heavy chains
-on mature B cell membranes

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IgE

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epsilon heavy chains
-lacks hinge region, 4 H domains
-binds to FCeR's on mast cells and basophils
-Type I allergic reactions

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types of light chains

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lambda and kappa
-k:l = 60:40

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IgG1

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-activates complement
-opsonization
-crosses placenta

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IgG2

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-activates complement
-opsonization
-doesn't cross placenta

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IgG3

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-activates complement
-opsonization
-crosses placenta

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IgG4

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-doesn't activate complement
-opsonization
-crosses placenta

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isotypes

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different classes of porteins in an individual

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allotypes

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same protein may be foreign in another member of species
-IgG, IgA2 heavy chains and all K lights

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idiotypes

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new antigenic determinant formed in the antigen-beinding site of newly-formed antibody

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chromosome 22

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where lambda chain locus is found in humans

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chromosome 2

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where K light chain locus is found in humans

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RAG-1 and 2

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recombinase enzymes that rearrange DNA in initial H/L chain formation and in receptor editing

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RSS

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reconbination signal sequences

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membrane IgM/D

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poly-adenylate sites 2 and 4

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secretory IgM/D

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poly adenylate sites 1 and 3

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class switching

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IgM to G (2a-IFNgamma)
IgM to A (IL-5 or TGFB)
IgM to IgG to E (IL-4 + 13/5)
-uses AID enzyme
-associated with somatic hypermutations, occurs after stimulation of cytokines and expression of CD40L on Tcell

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allelic exclusion

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Pro-B cell: H1-H2
Pre B cell: K1-K2-L1-L2

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genetic basis for Ab diversity

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-multiple V genes
-multiple VJ and VDJ combos
-variability in joining
-nucleotide addition
-somatic mutations
-combinatorial association of H and L

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Progentior B cell

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-VLA-4 : VCAM-1 (sc)
-c-Kit : SCF (sc)
-kinase activation = heavy chain VDJ rearrangement
-IL-7R : IL-7

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Precursor B cell

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-need IL-7 to drive proliferation
-mu heavy chain expressed with surrogate light chain
-CD25, pax-5 and BSAP are also expressed

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VCAM-1

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on stromal cell, binds VLA-4 on pro-B cell

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VLA-4

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on pro-Bell, binds VCAM-1 on stromal cell

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C-Kit

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on pro-Bell, binds SCF on stromal cell
-activates kinase that starts VDJ

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SCF

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on stromal cell (stem-cell factor), binds C-Kit on pro-B cell
-activates kinase that starts VDJ

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IL-7

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absolutely necessary to drive pre-B cell proliferation and survival

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surrogate light chain

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lambda-5 and Bpre-B

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Ig-alpha and beta

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signal-transducing heterodimers

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clonal deletion

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negative selection of self-reactive immature B-cells; can rescued if RAG still around "receptor editing"

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HLA

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human leukocyte antigens
aka MHC
on chromosome 6
I- ABC
II- DP, DM, DQ, DR

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other genes found in MHC locus

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TAP-1,2, LMP, complement (C4, C2, Factor B), cytokines (TNF)

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H2

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MHC in mouse
on chromosome 17
I-KDL
II-M, IA, IE

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ABC

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genes on chromosome 6 for MHC class I

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DP, DM, DQ, DR

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genes on chromosome 6 for MHC class II

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KDL

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mouse genes on chromosome 17 for MHC class I

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M, IA, IE

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mouse genes on chromosome 17 for MHC class II

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MHC class I

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3-domain alpha chain 45K + B2 microglobulin (15/2) 12K
-on all nucleated cells
-associate with CD8, on CTLs
-6 differen molecules per cell

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MHC class II

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alpha chain 34K + beta chain 29K
-on APC cells, macrophages, dendritic cells
-associate with CD4 on TH cells
-8 different molecules per cell

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immunoglobulin levels in fetus and infant

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maternal IgG until infection offurs in utero (IgM)
-3-12 mos = replacement with neonatal IgG and IgM

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transient hypogammaglobulinemia

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in newborns 3-6 mos after birth

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cytomegalovirus

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common virus for fetus and newborns
-also in polyclonal B cell autoimmunity activation and an HIV opportunistic infection

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treatment for immunodeficiency

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gamma globulin (except if IgA deficient), antibiotics, transfusions, thymic/bone marrow transplants, gene therapy

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primary immunodeficiences

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congenital and hereditary
-X-linked, autosomal recessive
-B and T cell
-IL-2, IL-7 receptor defects etc

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T cell immunodeficiency

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fungal, viral, protozoan infections
-appears right away

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B cell immunodeficiency

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bacterial infections
-appears after 3-6 mos

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Di George Syndrome

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thymic aplasia
-not genetic
-anergy (no T cells)
-defect from 3rd adn 4th pharyngeal pouches
Sx: no PTH, hypertelorism, micrognathia, facial and heart abnormalities
Tx: 10-14 week fetal thymic grafts

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Bruton's

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stop B cell development
-tyrosine kinase defect
-recessive X-linked
-appears 3-6 mos after birth

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hypertelorism

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wide-set eyes
Sx of Di George syndrome

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micrognathia

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small jaw
Sx of Di George syndrome

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CVH (common variable hypohammablogulinemia)

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-fairly common B cell immunodeficiency
-idiopathic
-mostly Ab defect, variable

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selective IgA deficiency

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-common B cell immunodeficiency
-respiratory, bowel infections
-can't treat with gamma globulin

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secondary/acquired immunodeficiency

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-ID is secondary to other conditions:
-malnutrition
-disease
-toxic therapy or agents
-viral agents

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T-cell leukemia

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viral infection of immunocompentent cells (acquired immunodeficiency)

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Epstein-Barr virus (EBV)

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viral infection of immunocompetent cell (acquired immunodeficiency)
-turns on polyclonal B cell activation (autoimm)
-antigenic mimicry for MS
Sx: kissing tonsils, leukoplakia

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HIV

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ssRNA retrovirus
gp120 binds to CD4 of Th cells, macrophages, microglia
-also needs chemokine co-receptors (CXCR4, CCR5) for fusion

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gp120

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HIV protein that binds with CD4

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SIVCPZ

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HIV-1

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SIVSM

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HIV-2 (sooty mangabeys)

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AIDS

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when TH cells are < 200/microlitres blood

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syncitium formation

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fusion of HIV-infected cell and normal CD4+ cell
-contributes greatly to low T cell count

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HIV infection progression

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2 weeks:acute phase, can see HIV antigen, no Ab's
2 months: start to see Ab against HIV (anti-gp40, -gp120, -p24)
years: when <200cells/uL = AIDS-->opportunistic infxn

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anti-p4

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Ab whose levels dip as HIV progresses into AIDS (pre-AIDS)

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ELISA

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test for HIV antibodies in blood
should do at least 2 in the span of 2 mos

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lymphoadenopathy

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pronounced enlargement of lymph nodes
Sx of pre-AIDS

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opportunistic infections of HIV

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pneumocystis carinii, Kaposi's sarcoma, candidiasis, CMV

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rheumatoid factor

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IgM anti-IgG and IgG anti-IgG
-forms immune complexes in the joints, and vessels

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fluorescein conjugated inti-IgG

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used to detect SLE-immune complex glomerulonephritis or Goodpastures (if in basement membrane of glom)

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rheumatoid arthritis

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non-organ specific autoimmune disease
Type III hypersensitivity
-rheumatoid factor