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Immunology- MICR360/860

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Jules Bordet
discoverer of complement (1870-1961)
Nobel Prize 1919
primary synthetic sources of complement
*monocytes/macrophages
*hepatocytes
Classical Complement Activation pathway
activated by antigen-antibody complexes
C1complex-C4//C4b-C2//C4b2a=C3 convertase-C3//C4b2a3b=C5 convertase
Alternative Complement Activation pathway
activated on microbial surfaces in the absence of antibody
C3/spon/C3b-Factor B-FactorD//C3bBb=C3 convertase-C3//C3bBbC3b=C5 convertase
Lectin Complement Activation pathway
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
First Line of Defense
Anatomic and Physiologic Barriers
defensins
cysteine-rich peptides, present in skin and abundant in neutrophil granules
neutrophil granules contain:
-defensins
-hypochlorous acid
-phagocyte oxidase
-iNOS
inflammatory barrier
first step in natrual/innate response
-vasodilation, increase in capillary permeability, influx of phagocytes
-erythema, edema, heat pain
natural/innate immune response
first wave of immune responses
1. inflammatory barrier
2. phagocytic barrier
erythema
redness
margination
leukocytes preparing to crawl through vessel wall
extravasation
leukocyte crawling through venule wall
phagocytic barrier
natural/innate response
-neutrolphils
-macrophages
-eosinophils
neutrophils
-early phagocytosis
-excellent killing (high respiratory burst)
-inflammation and tissue damage
macrophages
-efficient phagocytosis
-secretion of cytokines to stimulate inflammation and immune cells
NK cells
-natural killers
-non-phagocytic
-lysis of infected cells via Fas/FasL system
-activates macrophages
TLR-1
recognizes bacteria parasites
TLR-2
recognizes bacteria parasites, gram positive bacteria and fungi
TLR-3
recognizes dsRNA viruses
TLR-4
recognizes Gram-negative bacteria
TLR-5
recognizes flagellated bacteria
TLR-6
recognizes Gram-positive bacteria and fungi
TLR-7
recoginzes ssRNA viruses
TLR-8
recoginzes ssRNA viruses
TLR-9
recognizes bacteria dsDNA dinucleotides (viruses..)
PAMPS
pathogen-associated molecular patterns, which are recognized by TOLL-like receptors of innate immunity cells
opsonization
coating of a microbe in order for easier digestion by a phagocyte
-complement, antibodies (IgG1 and 3), CRP, collectin
respiratory burst
phagolysosome turns O2-->superoxide with phagocyte oxidase, Arginine-->NO with iNOS to kill microorganism
phagocyte oxidase
converts O2-->superoxides
iNOS
intracellular nitric oxide synthetase; converts Arginine-->NO
complement
30 different glycoprotein molecules
*innate protein
-kill microbes (C9 MAC attack)
-opsonize microbes
-activate leukocytes
collectin
mannose-binding lectin
*innate protein
-opsonizes MOs
-activates complement by binding with MASP-1 and 2
pentraxin
C-reactive protein
*innate protein
-acute phase protein, secreted by hepatocytes b/c of fever or damage mediators
-opsonizes
-activates complement (?)
innate soluble proteins
-complement, cytokines, CRP, collectin, lysozymes, coagulation factors
cardinal features of adaptive immune response
-specificity
-memory
-diersity
-specialization
-self-limitation
-discrimination
reticulo-endothelial system (RES)
aka mononuclear phagocyte system
-all areas of body with macrophages, I think
Kupffer cells
liver (MPS/RES)
mesangial cells
kidney (MPS/RES)
primary lymphoid organs
thymus and bone marrow
-where T and B cells develop
secondary lymphoid tissue
aka peripheral
tonsils and adenoids, lymph nodes, spleen, MALT, cutaneous tissues
high endothelial venule (HEV)
specialized blood vessel with no tigh junctions
-allows T and B cells to migrate into lymph node
lymph node cortex
contains follicles of B cells and germinal centres
also follicular dendritic cells
lymph node paracortex
contains T cells and interdigitating dendritic cells
lymph node medulla
contains medullary cords of B cells and plasma cells
langerhans cells
dendritic cells in the epidermis and mucousal membranes
-phagocytic/APC function
interstitial dendritic cells
dendritic cells that populate most organs
-phagocytic/APC function
interdigitating dendritic cells
dendritic cells found in T-cell areas of secondary lymphoid tissues and thymic medulla
-phagocytic/APC function
veiled cells
circulating dendritic cells found in blood and lymph
-phagocytic/APC function
follicular dendritic cells
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
marginal zone
in spleen, where B cells and dendritic cells are
periarterial lymphatic sheath (PALS)
in spleen, where T-cells are
M cell
microvilli cells
-anple antigens in lumen, bring them to B and T cells inside
MALT
mucous-associated lymphoid tissue
-biased toward IgA, have own specialized lymphocytes (mucosal homing receptors)
granulocytes
*contain inflammatory mediators in their granules
-neutrophils
-eosinophils
-basophils
characteristic B-cell markers
CR-1 and 2
B220 (CD45R)
B7
CD40
CR-1
-characteristic B-cell marker
-inhibits complement pathway
B220/CD45R
frequently used as a marker for B-cells
"leukocyte common antigen"
B7
important regulatory molecule
CD40
critical for survivial of antigen-stimulated B-cells
B cells fight against...
...extracellular phases of bacterial and viral infections, and toxins
T cells fight against...
fungal, parastice and intracellular viral and bacterial infections; tumour cells; transplated organs/tissues
immunogen
molecule that has the ability to evoke a specific immune response and can react with the resultant specific antibody
factors that influence immunogenicity
-foreignness
-molecular size > 10000Da
-molecular complexity
-degradability
-more particulate
-denatured
isogeneic/autologous
of own self
syngeneic
from same genes
allogeneic
from different individual of same species
xenogeneic
from different species
adjuvants
when mixed with antigen and injected, enhances the immunogenicity of that antigen only
aluminum potassium sulfate (alum)
used in vaccines with Bordetella pertussis
dinitrophenol (DNP)
the hapten with BSA
bovine serum albumin (BSA)
the carrier protein for DNP
factors affecting cross-reactivity
inhibiting:
-strong acidic groups
-glycoside groups
enhancing:
-nonionic radical groups
heteroclitic antibodies
higher affinity for cross-reacting epitopes than for their homologous epitope
multiple myeloma
monoclosal tumours of antibody-producing plasma cells
-also secrete Bence-Jones proteins
hybridomas
mutant myeloma cell line crossed with activated spleen cells from a mouse
-able to grow in HAT medium
ADCC
antibody-dependent cell-mediated cytotoxicity
-carried out by T-cells and NK cells
functions of immunoglobulins
*antigen binding
-fixation of complement
-->lysis of cells, clearance of immune complexes
-binds phagocytic cells, T-cells, NK cells, mast cells and basophils
hinge region
region at which the arms of teh Ab form a Y
-some flexibility here except in IgM and IgE
oligosaccharides
carbs N-linked to the C(H2) domain in most immunoglobulins
immunoglobulin superfamily
Ig, TCR, CD4, CD8, CD3, MHC class I and II
HVR/CDR
hypervariable/complementary determining regions
frameword regions
areas outside of HVR/CDRs in binding cleft of Ig
papain
cleaves Ig into 2Fab + Fc
pepsin
enzymes that cleaves Ig into F(ab)2
IgG
gamma heavy chains
-80% in serum
-activates complement
-opsonization
-crosses placenta
IgA
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
IgM
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
IgD
delta heavy chains
-on mature B cell membranes
IgE
epsilon heavy chains
-lacks hinge region, 4 H domains
-binds to FCeR's on mast cells and basophils
-Type I allergic reactions
types of light chains
lambda and kappa
-k:l = 60:40
IgG1
-activates complement
-opsonization
-crosses placenta
IgG2
-activates complement
-opsonization
-doesn't cross placenta
IgG3
-activates complement
-opsonization
-crosses placenta
IgG4
-doesn't activate complement
-opsonization
-crosses placenta
isotypes
different classes of porteins in an individual
allotypes
same protein may be foreign in another member of species
-IgG, IgA2 heavy chains and all K lights
idiotypes
new antigenic determinant formed in the antigen-beinding site of newly-formed antibody
chromosome 22
where lambda chain locus is found in humans
chromosome 2
where K light chain locus is found in humans
RAG-1 and 2
recombinase enzymes that rearrange DNA in initial H/L chain formation and in receptor editing
RSS
reconbination signal sequences
membrane IgM/D
poly-adenylate sites 2 and 4
secretory IgM/D
poly adenylate sites 1 and 3
class switching
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
allelic exclusion
Pro-B cell: H1-H2
Pre B cell: K1-K2-L1-L2
genetic basis for Ab diversity
-multiple V genes
-multiple VJ and VDJ combos
-variability in joining
-nucleotide addition
-somatic mutations
-combinatorial association of H and L
Progentior B cell
-VLA-4 : VCAM-1 (sc)
-c-Kit : SCF (sc)
-kinase activation = heavy chain VDJ rearrangement
-IL-7R : IL-7
Precursor B cell
-need IL-7 to drive proliferation
-mu heavy chain expressed with surrogate light chain
-CD25, pax-5 and BSAP are also expressed
VCAM-1
on stromal cell, binds VLA-4 on pro-B cell
VLA-4
on pro-Bell, binds VCAM-1 on stromal cell
C-Kit
on pro-Bell, binds SCF on stromal cell
-activates kinase that starts VDJ
SCF
on stromal cell (stem-cell factor), binds C-Kit on pro-B cell
-activates kinase that starts VDJ
IL-7
absolutely necessary to drive pre-B cell proliferation and survival
surrogate light chain
lambda-5 and Bpre-B
Ig-alpha and beta
signal-transducing heterodimers
clonal deletion
negative selection of self-reactive immature B-cells; can rescued if RAG still around "receptor editing"
HLA
human leukocyte antigens
aka MHC
on chromosome 6
I- ABC
II- DP, DM, DQ, DR
other genes found in MHC locus
TAP-1,2, LMP, complement (C4, C2, Factor B), cytokines (TNF)
H2
MHC in mouse
on chromosome 17
I-KDL
II-M, IA, IE
ABC
genes on chromosome 6 for MHC class I
DP, DM, DQ, DR
genes on chromosome 6 for MHC class II
KDL
mouse genes on chromosome 17 for MHC class I
M, IA, IE
mouse genes on chromosome 17 for MHC class II
MHC class I
3-domain alpha chain 45K + B2 microglobulin (15/2) 12K
-on all nucleated cells
-associate with CD8, on CTLs
-6 differen molecules per cell
MHC class II
alpha chain 34K + beta chain 29K
-on APC cells, macrophages, dendritic cells
-associate with CD4 on TH cells
-8 different molecules per cell
immunoglobulin levels in fetus and infant
maternal IgG until infection offurs in utero (IgM)
-3-12 mos = replacement with neonatal IgG and IgM
transient hypogammaglobulinemia
in newborns 3-6 mos after birth
cytomegalovirus
common virus for fetus and newborns
-also in polyclonal B cell autoimmunity activation and an HIV opportunistic infection
treatment for immunodeficiency
gamma globulin (except if IgA deficient), antibiotics, transfusions, thymic/bone marrow transplants, gene therapy
primary immunodeficiences
congenital and hereditary
-X-linked, autosomal recessive
-B and T cell
-IL-2, IL-7 receptor defects etc
T cell immunodeficiency
fungal, viral, protozoan infections
-appears right away
B cell immunodeficiency
bacterial infections
-appears after 3-6 mos
Di George Syndrome
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
Bruton's
stop B cell development
-tyrosine kinase defect
-recessive X-linked
-appears 3-6 mos after birth
hypertelorism
wide-set eyes
Sx of Di George syndrome
micrognathia
small jaw
Sx of Di George syndrome
CVH (common variable hypohammablogulinemia)
-fairly common B cell immunodeficiency
-idiopathic
-mostly Ab defect, variable
selective IgA deficiency
-common B cell immunodeficiency
-respiratory, bowel infections
-can't treat with gamma globulin
secondary/acquired immunodeficiency
-ID is secondary to other conditions:
-malnutrition
-disease
-toxic therapy or agents
-viral agents
T-cell leukemia
viral infection of immunocompentent cells (acquired immunodeficiency)
Epstein-Barr virus (EBV)
viral infection of immunocompetent cell (acquired immunodeficiency)
-turns on polyclonal B cell activation (autoimm)
-antigenic mimicry for MS
Sx: kissing tonsils, leukoplakia
HIV
ssRNA retrovirus
gp120 binds to CD4 of Th cells, macrophages, microglia
-also needs chemokine co-receptors (CXCR4, CCR5) for fusion
gp120
HIV protein that binds with CD4
SIVCPZ
HIV-1
SIVSM
HIV-2 (sooty mangabeys)
AIDS
when TH cells are < 200/microlitres blood
syncitium formation
fusion of HIV-infected cell and normal CD4+ cell
-contributes greatly to low T cell count
HIV infection progression
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
anti-p4
Ab whose levels dip as HIV progresses into AIDS (pre-AIDS)
ELISA
test for HIV antibodies in blood
should do at least 2 in the span of 2 mos
lymphoadenopathy
pronounced enlargement of lymph nodes
Sx of pre-AIDS
opportunistic infections of HIV
pneumocystis carinii, Kaposi's sarcoma, candidiasis, CMV
rheumatoid factor
IgM anti-IgG and IgG anti-IgG
-forms immune complexes in the joints, and vessels
fluorescein conjugated inti-IgG
used to detect SLE-immune complex glomerulonephritis or Goodpastures (if in basement membrane of glom)
rheumatoid arthritis
non-organ specific autoimmune disease
Type III hypersensitivity
-rheumatoid factor
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