Week 4 Flashcards
T cell responses are self-MHC limited
T cell receptors only recognize antigens when presented by self-MHC; killer T cells in mouse will only recognize and kill infected cells in which antigen is presented by self-MHC
Development and selection of T lymphocyte
Immature T cell in thymus with double positive expression
Positive selection- checks all T cells for ability to recognize peptides self-MHC molecules, and those that don’t do not get a survival signal
Negative selection- T cells that have high affinity for peptide/self-MHC complex do not receive a survival signal.
Mature T cells go into thymic medullary
Signal transduction in T cell receptor
alpha/beta chain harbor antigen binding site, non-covalently associated epsilon, gamma, zeta, and delta subunits (CD3), receptor activation triggers downstream cascade that results in the gene regulation of cytokines
Signal transduction in B cell receptor
Antigen binds to IgM receptor, C3d attached to antigen binds to CD21 (complement receptor), ITAMs are phosphorylated in the cytoplasmic region of the IgM associated alpha and beta chains, SyK recruitment, upregulate transcription factors NF-kB, NFAT, c-myc, AP-1
Effector functions- clonal proliferation (mitosis), increased expression of cytokine receptors, secretion of IgM, migration out of lymphoid follicles
T cells and cytokines responsible for humoral response
B cell presents antigen/MHC and expresses costimulatory B7 molecule for CD4 T cell activation; T cell expresses CD40L and cytokines for B cell class switching, affinity maturation, switch to secretion, memory cells
Effector functions of antibodies
neutralization, opsonization, phagocytosis, antibody-dependent cytotoxicity, complement activation
Effector functions of different Ab isotypes
IgM- serves as BCR on naive B cells, low affinity and can be fixed by complement
IgD- found on naive B cells as a membrane bound receptor, not secreted
IgG- opsonization for phagocytosis, activation of the classical pathway of complement, antibody-dependent cell-mediated, neonatal immunity, feedback inhibition of B cell responses by crosslinking the BCR with inhibitory FC receptors expressed on B cells
IgA- mucosal immunity, secreted across mucosal epithelium onto mucosal surfaces, neonatal immunity, and secreted into breast milk
IgE- mediates antibody dependent cytotoxicity by eosinophils in the immune response against extracellular parasites, and is involved in the regulation of mast cell reponses
Regulation of complement system
C1 inhibitor- serine protease inhibitor that directly inhibits C1r and C1s
Factor I- inactivates C3b
Factor H- directly inhibits function of the alternative C3 convertase by binding C3b and displacing Bb
Delay-accelerating factor- expressed on endothelial and epithelial cells as GPI linked proteins that inhibit the formation of C3 convertase
TCR/CD3 complex
TCR alpha/beta chains have short cytoplasmic domains, the CD3 peptide (gamma, delta, epsilon, zeta) associated with TCR provides the signal transduction function, each contains an ITAM that gets phosphorylated to recuirt ZAP70 which is a downstream effector that eventually leads to upregulation of transcription factors
Understand the role of CD4/CD8 co-receptors, adhesion molecules (e.g. LFA-1) and co-stimulatory molecules (e.g. CD28 and CD40L) in the regulation of T cell activation
CD4/CD8 co-receptors are in very close proximity with TCR-antigen complex, expresses a tyrosine kinase p56Ick that promotes phosphorylation of ITAM and recruitment of ZAP70
CD28- expressed on all T cells and binds to B7 ligands expressed on activated antigen presenting cells, increases expression of cytokine and genes related to clonal expansion and differentiation
CD40L- expressed on T cells, CD40 found on dendritic cells, B cells, and macrophages, binding enhances antimicrobial activity of macrophages and upregulation of B7, and increases IL12, 23 expression
LFA-1- adhesion molecule to maintain TCR-antigen interaction, binds to ICAM-1
Understand the general features of cell mediated immune responses and delayed-type hypersensitivty
Cell mediated immunity
1) activation of macrophages by interferon gamma secreted by TH1 cells and GM-CSF and IL17 secreted by TH17 cells
2) lysis of infected cells by CD8+ CTL
Understand role of Th-1 derived cytokines in the regulation of DTH responses
naive CD4 cells in the lymph node get activated by antigen and up-regulate E/P selectin ICAM/VCAM-1 and CXCL10 to leave via efferent lymphatic vessel into site of inflammation using selectins and chemokine receptors, extravasate into inflamed tissue, interact with antigen, and secrete interferon gamma
DTH- macrophage accumulation at side of antigen challenge (perivascular)
Effects of cytokines on macrophage function
Activation of macrophages by CD4 effector cells: interferon gamma, upregulation of MHC and costimulatory molecules, secretion of IL12, TNF, chemokines, and IL1 by macrophage
Activation and differentiation of CTL’s
APC brings processed antigen presented by MHC Class I to naive CD8 cell along with co-stimulatory molecules, cytokines IL-2 and IFNgamma are needed to achieve activation, proliferation and differentiation
Mech. of cell-mediated lysis
Perforin mediated cell lysis
FasL mediated apoptotic cell lysis
Mech. of central tolerance for both B and T lymphocytes
T cell- positive and negative selection in the thymus
B cell- negative selection with induced apoptosis, those that escape outside of the bone marrow undergo receptor editing (antigen binding site)
Mech. of peripheral tolerance
Clonal anergy (T)- when naive T cell encounters self-antigen presented by self-MHC with no co-stimulatory signal, T cell becomes unresponsive, even if with reintroduction of antigen presented with co-stimulatory Clonal anergy (B)- high exposure to self-antigen inhibits BCR and prevents B cell entry into lymphoid follicles Clonal deletion- T cells that have high exposure to self-antigen in the periphery are induced to apoptose via FasL-fas binding and downstream cascade of apoptotic effectors Treg cells- arise from antigen- T cell interaction, expresses Foxp3, may exert effect via IL-10 and TGF-beta Other examples- Th1, Th2, and Th17 all cross-regulate each other
Understand the pathophysiology of autoimmunity: genetic susceptibility, role of infection, and how loss of tolerance contributes, specific disease examples
Inappropriate stimulation of co-stimulatory molecules due to infection
Epitope spreading due to local infection
Molecular Mimicry
Mutation or dysfunction of regulatory molecules (Fas, Foxp3)
Age, sex, genetic factors (MHC variants)
Mech. of treatment of autoimmunity
IV administration of soluble Ag, IV administration of Ag conjugated with apoptotic APC or PLG, Altered peptide ligands (prevent phosphorylation of CD3)
Immunology and genetics of graft rejection
Graft rejection is mediated by T lymphocytes or antibodies
Allogeneic and some inbred circumstances lead to graft rejection
Mech. of alloantigen presentation and recognition
T-cell recognition of alloantigen
1) Direct- allo-MHC or allo-MHC+peptide
2) Indirect- allo-MHC is phagocytized/chopped up into peptides, loaded onto donor MHC on donor APC
Understand the effector mechanisms involved in hyperactute, acute and chronic graft rejection
Hyperacute-mediated by pre-existing Ab, bind to donor endothelial cells and cause Ab-mediated hemmorhage and thrombotic occlusion of the graft vasculature, IgM (ABO carbs) or IgG (other alloantigens)
Acute- CD8 cells reactive with alloantigens on graft endothelium, result in destruction of parenchyma and epithelium
Chronic- CD4 cells–> Macrophages–> Cytokines–> Smooth muscle proliferation around the vasculature supporting the donor tissue
Methods used to limit graft rejection
Match ABO blood types
Cross match for pre-existing antibodies against donor
Match MHC alleles (kidney/liver)
Immunosuppression
Blocking of activity of co-stimulatory molecules
Bone Marrow transplant
- Patient with defects in hemopoeietic system or disseminated tumors are treated with chemotherapy and radiation to deplete own lymphoid compartment and bone marrow
- Stem cells (mobilized or in bone marrow) of donor is grafted
- Host and recipient must be MHC and sex matched
GVHD- when host T cells build an immune response against alloantigens of the host
Acute- cell necrosis of skin, liver and GI tract
Chronic- fibrosis of skin, liver and GI tract
Tumor evasion
Antigen-loss variant of tumor cell
Mutations of MHC genes
Expression of immunosupressors (TGFbeta and PD-L1
Chemical Mediators
Vasoactivators- histamine, secretion
Proteins- complement, kinins, cytokines/chemokines
Lipids- leukotrienes, prostaglandins, PAF
IgE-antigen/C3a+ C5a
Histamine release from mast cells/basophils
1) arteriolar dilation with increased blood flow
2) contraction of venular endothelial clles
3) vascular permeability
Released from membrane of leukocytes–> PAF
1) vasodilation
2) increased vascular permeability
3) adherence of leukocytes to vascular endothelium
4) chemotaxis
5) increased prostaglandin synthesis
Membrane phospholipids
C5a–> Phospholipase A–> arachidonic acid
1) PGD/PGE/PGF–> vasodilation and potentiate edema
2) Leukotrienes–> vasodilation, inhibit neutrophil chemotaxis, stimulate monocyte adhesion
Cytokine release
Activated macrophage/monocyte–> IL1–> NFkB–> MAPK
1) Endothelial synthesis of adhesion molecules, prostaglandins, nitric oxide
2) Endothelial retraction/increased vascular permeability
3) fever
4) fibrosis
Chemokines
1) Arrest and firm adhesion
2) Integrin avidity
3) chemoattract for leukocytes
Cytokine
TNF- responds to macrophages and lymphocytes, binds to TNFR1/2, NFkB, MAPK
1) CCL2- monocyte chemoattractant protein
2) CXC8- polymorphonuclear leukocyte attractant (neutrophils)
