Immunology Flashcards
What is MHC?
What are the defining features of MHC?
MHC molecules are membrane proteins on APCs that display processed peptide antigens for recognition by T cells.
Key properties:
- MHC genes are highly polymorphic - different individuals are able to present and respond to different microbial peptides. Different polymorphic variants are inherited and not generated de novo.
- Co-dominant expression: alleles inherited from both parents are expressed equally - increases number of different MHC molecules that can present peptides
- Class I are expressed on all nucleated cells, Class II are expressed on professional APCs
Nomenclature of HLA genes and proteins
Class I has 3 polymorphic gene loci = HLA-A, HLA-B, HLA-C, one set of genes inherited from each parent. Therefore, can express 6 different class I molecules
Class II: every individual inherits from each parent 2 genes for a-chain and B-chain of HLA-DP, DQ, 1 or 2 for DRB and 1 for DRa (e.g. 2DPa, 2DPB, 2DQa, 2DQB, 4DRB, 2DRa) - more complex elaboration of protein
MHC haplotype = set of MHC alleles present on each chromosome
What is the difference between MHC Class I and II?
MHC Class I: present on all nucleated cells, binds peptides derived from degraded intracellular proteins (cytosolic antigens) and presents to CD8+ lymphocytes (Ix8=8)
MHC Class II: only present on professional ABCs and thymic epithelium, binds extracellular microbial peptides that have been endocytosed from external environment (IIx4=8)
Mechanisms of viral subversion of Ag presentation
HSV: produces TAP inhibitor protein
- TAP-1 & TAP2 = transports free cytoplasmic Ag into ER so it can be bound to MHC Class I
Adenovirus: produces protein that anchors MHC in ER - prevents surface expression of MHC
CMV: accelerates transport of peptides out of ER - reduces the chance of binding to MHC
What is the role of CCR7?
CCR7 is the chemokine receptor expressed on activated dendritic cells. It is specific for chemoattractants produced by lymphoid organ endothelium and stromal cells of the T cell zone in lymph nodes. Therefore, attracts activated DCs from peripheral sites to lymph nodes where it meets and stimulates naive T cells.
Are plasmacytoid dendritic cells different to classical dendritic cells?
Yes
Plasmacytoid DCs respond to viral infections
1. Receptors: expresses TLRs in endosomes, RLRs in the cytoplasm
2. Releases type 1 interferon (a and B) in response to viral state - inhibits viral replication, induce antiviral state, induces apoptosis of infected cells, increases NK cell-mediated lysis, upregulates MHC Class I
What are the signs of DC maturation?
- Upregulation of MHC Class II and increased stability of structure
- Increased Ag processing activity
- Upregulation of costimulatory molecules (B7.1 and 7.2), adhesion molecules, signalling molecules
- Production of cytokines
- Further recruitment of DC precursors to periphery
What are toll-like receptors?
TLRs are pattern recognition receptors that bind pathogen-associated molecular patterns (PAMPs = highly conserved structures shared by groups of microorganisms)
An integral part of innate immune system -
1. TLRs are present on phagocytes and bind microbes/Ag
2. Activates transcription factors NF-kB and IRF
3. Stimulates production of inflammatory cytokines, chemokines and co-stimulatory molecules
I.e. kick starts innate immune response
Describe the TLRs
TLR 1, 6 binds lipopeptides
TLR 2 binds peptidoglycan and glycoplipids
TLR 3, 7, 8 binds SS-RNA and DS-RNA viruses
TLR 4 binds LPS
TLR 5 binds bacterial flagellin
TLR 9 binds unmethylated CpG DNA
TLRs 3, 7, 8, 9 are in endosomes, rest are on plasma membrane
What is the significance of TLR 4?
TLR 4 binds bacterial LPS in concert with CD14
Responsible for shock in gram negative sepsis
TLR 3 pathway deficiency
TLR 3 is expressed in the CNS
Children with TLR 3 deficiency can develop HSV encephalitis. It usually controls the interferon response to dsRNA intermediates of HSV1
Important cytokines involved in innate immune system
IL-1 IL-6 TNF IL-12 IFN-Y Type 1 IFN
What are the molecular differences between naive and memory B cells?
Naive B cells:
- IgM(lo), IgD (hi)
- CD5- / CD23+ / CD27-
- Unmutated Ig V genes
- Lower affinity for Ag
- Higher threshold for activation
- Lack of expression of co-stim molecules
- Located in follicles of lymphoid organ
Memory B cells:
- IgM only, IgM(hi)/IgD (lo), IgG, IgA, IgE
- CD5- / CD23+ / CD 27+
- Mutated Ig V genes
- Higher affinity for Ag
- Lower threshold for activation
- Expresses costimulatory molecule CD 80/86
- Located in marginal zone of lymphoid organs ?
What are the major functions of T lymphocytes?
- Activate phagocytes
- Kill infected cells (infected with intracellular microbes)
- Help B cells produce antibodies and mount humoral response
Function of antibodies
- Neutralisation of microbes and/or toxins
- Promote opsonisation
- Antibody-mediated cellular cytotoxicity (mediated by NK cells and CD8+ T cells)
- Complement activation (classical pathway)
- Lysis of microbes
- Phagocytosis of microbes opsonised with complement fragments
- Promotes inflammation and further release of cytokines - Fight helminth infections, hypersensitivity reactions
Growth factor for T cells
IL-2
CD markers (clusters of differentiation) for different cell types
T cells: CD4 (helper), CD8 (cytotoxic), CD2+, CD3+
Mature B cells: CD 19+, CD 20+
- Memory B cells: CD27+
NK cells: CD16+, CD56+
Testing response to vaccination (polysaccharide)
Response to polysaccharide vaccines = testing T cell-independent B cell response
E.g. Hib, meningococcal, pneumococcal polysaccharide vaccine
Response to polysaccharide Ag (TI-2):
- TIR: binds BCR (IgM) on plasma membrane surface –> cross-linking of immunoglobulins –> rapid production of simple, short-lived plasma cells producing low affinity IgM. Unable to class switch, no memory cells.
- -> Method of assessing B cells on their own
- -> Only useful in children >2yo (<2yo unable to mount response to polysaccharide vaccines)
Testing response to vaccination (conjugate)
Response to conjugate vaccines = testing T cell-dependent B cell response
E.g. Hib, meningococcal, pneumococcal with carrier protein (tetanus toxoid or diphtheria toxoid) attached to polysaccharide Ag
B cells process the small amount of carrier protein and present to T cells:
- T cell produces IL-4
- Co-stimulation: production of CD40-CD40L –> greater response with production of IgG with stronger affinity, formation of memory cells
Diagnostic criteria for CVID
At least 1 of the following:
- Increased susceptibility to infections
- Granulomatous disease
- Autoimmune manifestations
- Unexplained polyclonal lymphoproliferation
- Affected family member with Ab deficiency
AND:
1. Marked decrease of IgG and/or IgA with or without IgM deficiency (<2SD normal for age)
AND:
- Poor Ab response to vaccine OR
- Low levels of memory B cells
AND:
1. Secondary causes of hypogammaglobulinemia are excluded
AND:
1. Diagnosis established >4yrs of age (Sx can be present before this time)
AND:
1. No evidence of profound T cell deficiency
What confers a poor prognosis for CVID
Presence of lymphadenopathy and splenomegaly
T regulatory cells
- Important in T cell tolerance = unresponsiveness to self
- CD4 T cells that also express IL-2Ra (CD25), CTLA4 and IL-10
- Function: suppresses activation and effector functions of mature self-reactive lymphocytes - maintains self-tolerance in peripheral tissues
- Foxp3 is the master regulator of Treg cells - responsible for their development and function
- -> Reinforces regulatory phenotype: CTLA4, IL-10
- -> Blocks transcription of IL-2 gene
- Lack of Treg cells –> overactivity of immune function leading to autoimmunity, allergy, lymphoproliferation
