First Aid, Chapter 1 Immune mechanism: antigens, MHC, and Tolerance Flashcards
What is the hapten- carrier effect?
Small-molecule antigen requires covalent linkage to a larger carrier to stimulate adaptive immune response. The process is achieved in collaboration between hapten-specific B cells and carrier-specific T cells. This is the basis of developing conjugated vaccines.
What are the common superantigens and related diseases?
SEB and SEC cause food poisoning; TSST and SPE-C cause toxic shock (Abbreviations: SEB, staphylococcal enterotoxin B; SEC, staphylococcal enterotoxin C; TSST, toxic shock syndrome toxin; SPE-C, streptococcal pyrogenic exotoxins C.syndrome.)
Where do superantigens bind?
Superantigens bind the Vβ region of TCRs (CDR4) and outside of the peptide-binding groove on the MHC molecule.
Describe how conjugated vaccines work and give some examples.
Conjugated vaccines are T-independent antigens linked to a carrier protein, which can trigger a T- dependent response and memory. Examples of conjugated vaccines include 13-valent pneumococcal vaccine (Prevnar 13), Hib vaccines, and meningococcal vaccines (MCV4–Menactra and Menveo).
Which type of T cells recognizes lipid antigens and what is the molecule involved?
Natural killer T (NKT) cells and CD1 molecule.
What are the binding sites for TCR on MHC class I and class II molecules, respectively? Are the binding sites polymorphic or non-polymorphic?
α3 binds CD8 and β2 binds CD4. Non-polymorphic.
What are the MHC class 1 genes?
HLA A, B, and C.
What are the MHC class 2 genes?
HLA- DP, DQ, DR.
What are the MHC class 1 polypeptide chains (domains)?
α chain (α1, α2, α3) β2-microglobulin.
What are the MHC class 2 polypeptide chains (domains)?
α chain (α1, α2) β chain (β1, β2).
What are the MHC class 1 peptide binding site and are they polymorphic or non-polymorphic?
α1 and α2 (polymorphic).
What are the MHC class 2 peptide binding site and are they polymorphic or non-polymorphic?
α1 and β1 (polymorphic).
How many amino acids go in the peptide binding cleft for MHC class 1?
Peptides 8–11 amino acids.
How many amino acids go in the peptide binding cleft for MHC class 2?
Peptides 10–30 amino acids.
Is the antigen sampling for MHC class 1 intracellular or extracellular?
Intracellular.
Is the antigen sampling for MHC class 2 intracellular or extracellular?
Extracellular.
Which cells express MHC class 1?
Most nucleated cells.
Which cells express MHC class 2?
APC (dendritic cells, macrophages, and B lymphocytes), thymic epithelia, and activated T lymphocytes.
What are the inducing cytokines for MHC class 1?
Interferon (IFN)α, IFNβ, and IFNγ.
What are the inducing cytokines for MHC class 2?
IFNγ.
Describe the MHC 1 presentation pathway.
MHC I Pathway
-Newly synthesized MHC class I polypeptides remain sequestered in the endoplasmic reticulum by interacting with calnexin, calreticulin, Erp57, and tapasin.
-Cytoplasmic proteins that enter the cytoplasm are degraded to antigenic peptides by the proteasome:
o The proteasome is a multisubunit proteinase. Four seven-membrane rings
have catalytic subunits.
o Examples of subunits are: Low-molecular-mass polypeptide (LMP) 7 and
LMP2.
o LMPs are encoded in MHC class II locus.
Antigenic peptides are transported into the endoplasmic reticulum by transporter of antigenic-processing (TAP) proteins.
o Energy-dependent transport of peptides.
o Composed of two subunits: TAP1 and TAP2, both of which must be
present for function.
o TAP proteins are encoded in MHC class II locus.
Antigenic peptides are loaded onto newly synthesized MHC class I polypeptides.
MHC class I and antigenic peptide are transported to cell surface.
Stable MHC class I expression requires presence of antigenic peptide.
How to MHC class 1 polypeptides remain sequestered in the endoplasmic reticulum?
interacting with calnexin, calreticulin, Erp57, and tapasin.
How are cytoplasmic proteins degraded in the MHC class 1 pathway?
Cytoplasmic proteins that enter the cytoplasm are degraded to antigenic peptides by the proteasome.
How are antigenic peptides transported into the endoplasmic reticulum in the MHC class 1 pathway?
By transporter of antigenic-processing (TAP) proteins.
o Energy-dependent transport of peptides.
o Composed of two subunits: TAP1 and TAP2, both of which must be
present for function.
o TAP proteins are encoded in MHC class II locus.
Name 2 viruses that evade MHC class 1 presentation and describe how.
Herpes simplex virus (HSV) can block TAP transportation, and cytomegalovirus (CMV) can remove MHC class I molecule from ER.
MHC class I molecule presents which type of antigens and where does the antigen-MHC class I loading happen?
Intracellular antigens (e.g., viral antigen in cytoplasm) and the loading site is endoplasmic reticulum (ER).
Describe the MHC II presentation pathway.
MHC II Pathway Extracellular antigen is endocytosed and compartmentalized in cytosolic phagosomes. Phagosomes fuse with lysosomes. The resulting phagolysosome degrades the microbe into antigenic peptides by endosomal and lysosomal proteases (cathepsins). Newly synthesized MHC class II molecules are synthesized in the ER and transported to the phagolysosome, forming the MHC class II vesicle. The MHC class II-binding cleft is occupied by the invariant chain (Ii) prior to peptide loading. In the MHC class II vesicle, the Ii is degraded by proteolytic enzymes, leaving behind a short peptide named class II-associated invariant chain peptide (CLIP). HLA-DM removes CLIP and allows antigenic peptides to be loaded in the MHC-binding cleft. MHC class II and peptide are transported to cell surface. Stable MHC class II expression requires presence of antigenic peptide.
What is HLA-DM? Where is it located? What is its function?
HLA-DM is an intracellular protein involved in MHC class II antigen processing and does not present antigenic peptides nor is it a component of MHC class II. HLA-DM removes CLIP and allows antigenic peptides to be loaded in the MHC-binding cleft.
What is the invariant chain (li) and where is it located? What happens to it and what does it become?
The MHC class II-binding cleft is occupied by the invariant chain (Ii) prior to peptide loading. In the MHC class II vesicle, the Ii is degraded by proteolytic enzymes, leaving behind a short peptide named class II-associated invariant chain peptide (CLIP). HLA-DM removes CLIP and allows antigenic peptides to be loaded in the MHC-binding cleft.
What are the bare lymphocyte syndrome defects? What are the mutations in them? What is the inheritance?
MHC class 1 deficiency is caused by mutations in genes encoding for TAP— essential for MHC class I expression. MHC class 2 deficiency is caused by mutations in genes encoding for mutations in several transcription factors required for MHC class II expression: MHC2TA, RFX5, FRXAP, and FRXANK Autosomal recessive.
What are the clinical features of the bare lymphocyte syndromes?
MHC class 1 deficiency: Sinopulmonary infections, granulomatous skin lesions, and necrobiosis lipoidica
MHC class 2 deficiency: Diarrhea, hepatosplenomegaly, transaminitis, sclerosing cholangitis (Cryptosporidium parvum), pulmonary infections (Pneumocystis jiroveci, encapsulated bacteria, Herpesviridae, and RSV), and meningitis
What are the lab findings of the MHC class 1 and 2 deficiencies?
MHC class 1 deficiency: CD8 lymphopenia, PBMC on flow cytometry lack MHC class
MHC class 2 deficiency: CD4 lymphopenia (reversed CD4:CD8) Lack of HLA DR/DP/DQ on lymphocytes, DTH Hypogammaglobulinemia Absent germinal centers from lymph nodes
What is the treatment for MHC class 1 and 2 deficiencies?
MHC class 1 deficiency: Treat pulmonary infections like CF (aggressive toileting and chest PT)
MHC class 2 deficiency: Hematopoietic stem cell transplantation (HSCT)
MHC class II molecule presents which type of antigens and where does the antigen-MHC class II loading happen?
Extracellular antigens (e.g., antigens from phagocytosed bacteria) and loading site is phagolysosome.
What is autoimmune polyglandular syndrome and what gene is mutated in it?
Mutation in the AIRE gene produces disorders such as autoimmune polyglandular syndrome (APS). Lymphocytes are not deleted or tolerized to endocrine-related selfantigens. The endocrine organs are attacked by autoreactive T lymphocytes and autoantibodies.
Describe central T-Lymphocyte Tolerance.
1) T-lymphocyte precursor is exposed to a self-antigen in the thymus.
2) two fates: apoptosis, which is also known as negative selection, or development into a regulatory T (Treg) cells that migrate to the periphery.
3) The thymus presents self-antigens through thymic antigen-presenting lymphocytes that process antigen in the context of HLA class I and II.
4) AIRE promotes expression of nonthymic antigens in the thymus.
What factors promote negative selection in central T-lymphocyte Tolerance?
High concentration and high affinity promote negative selection.
What does the autoimmune regulatry gene (AIRE) do?
The autoimmune regulatory gene (AIRE) is expressed in the thymus. This gene promotes expression of nonthymic tissue antigens in the thymus.
Describe central B-lymphocyte tolerance.
1) the precursor B lymphocyte is exposed to a self-antigen in the bone marrow during development.
2) three fates: apoptosis (negative selection), receptor editing, or anergy
Describe receptor editing, which type of tolerance does this occur in?
Receptor editing involves reactivation of RAG1 and RAG2 when a high-affinity self-antigen is recognized by a B-cell receptor (BCR). The RAG enzymes will delete the previously rearranged VκJκ exon and give the BCR a new light chain. As a result, the selfreactive immature B cell will have a new specificity. If both recombinations recognize a self-antigen (failure of editing), the immature B lymphocyte will be deleted by apoptosis. In low antigen concentration, the B lymphocyte may become anergic to the self-antigen.
In peripheral T-lymphocyte tolerance, what are the possible fates?
Anergy, deletion, or regulation.
What two factors cause anergy in peripheral T-lymphocyte tolerance? Name 4 ways anergy is maintained.
Lack of a second signal or lack of innate costimulation (eg. microenvironment).
Maintained by
1) blockade of TCR signaling
2) ubiquitin ligases (target proteins for degradation)
3) inhibitor costimulatory molecules (eg. CTLA-4 and PD-1).
4) dendritic cells present self-antigen without expression of costimulatory molecules.
Describe how dendritic cells maintain anergy.
Inactivated or immature dendritic cells present self-antigen, but do not express receptors. Therefore, when they present to T-lymphocytes there is no 2nd signal and this results in tolerance. Presentation is ongoing.
What types of t-lymphoctes develop in the thymus with weak, intermediate, and strong binding between the cells and self-peptide/MHC complex respectively.
Weak binding - positive selection (effector cells)
Intermediate binding - Treg
Strong binding - apoptosis (negative selection)
What is the result of lack of costimulation or lack of an innate system response with respect to T-lymphoctyes?
Anergy:
explanation:
Lack of costimulation, or lack of an innate immune system response to the antigen, blunts the required upregulation to achieve costimulation (i.e., a second signal). T lymphocytes recognize the antigen, but receive no support to activate. After repeated recognition without costimulation, the lymphocyte becomes unresponsive to that antigen (i.e., anergic). Once a cell is anergic, costimulation will not restore activation.
What chains are rearranged in B cell receptor editing and in what order?
κ light chains are rearranged first. If receptor editing is needed, a λ light chain will be used.
What do Tregs express?
CD4, CD25 (IL-2R alpha chain), and FOX P3.
What cytokines do Tregs survival depend on?
IL-2 and TGFB.
What cytokines maintain tolerance or regulation of Tregs? And what cells do the cytokines target?
IL-10 and TGFB. IL-10 targets macrophages and dendritic cells and TGFB inhibits lymphocytes and macrophages.
What is Bim? How is it activated?
A propaptotic member of the Bcl-2 protein family. Activated by T-lymphocytes that repeatedly recognize self-antigens without costimulation.
What pathway does Bim cause apoptosis through?
Mitochondrial pathway.
What is the CD name for FasL?
CD95L
Where is FasL located?
On the T lymphocyte.
Where is FasL upregluated? What does it do?
Activated on repeatedly activated T lymphocytes. FasL interacts with Fas (CD95) on the same cell or nearby cells. Either deletes a self reactive T lympocyte or causes death of an activated cell. Downregulates the immune response.
What system does Fas: FasL signal through?
Caspase system.
What do FoxP3 mutations cause? Describe it?
FoxP3 mutation in human causes immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, which is a fatal autoimmune disorder characterized by a triad of watery diarrhea, eczema, and endocrinopathy.
What do mutations in Fas or caspase 10 cause?
Autoimmune lymphoproliferative syndrome (ALPS). The lymphocytes do not know when to die. They accumulate in the lymph organs. There is a lack of tolerance, producing autoimmune problems.
Why are B cells not activated without the help of Tcells?
Antigens cannot cross-link the BCR on their own, so B cells become anergic or are induced to apoptosis.
What is downregulated with chronic antigen recognition that inhibits B-lymphocyte honming and interaction with T lymphyocytes? What is the end result?
CXCR5 is downregulated, yields B cell apoptosis.
What chromosome are genes that encode MHC located on? On what arm? Where is the B2 microglobulin chain encoded?
Genes that encode MHC molecules are encoded on the short arm of chromosome 6, whereas the β2-microglobulin chain is encoded on chromosome 15.
What else does the MHC genome encode in addition to MHC polypeptides?
In addition to encoding the MHC polypeptides, the MHC genome encodes proteins involved in the processing of peptides that occupy the peptide-binding clefts.
What does the class III region of the MHC genome encode?
- Proteins of the complement system: Factor B, C4a, C4b, and C2
- Cytokines: Tumor necrosis factor (TNF)α, and lymphotoxins α and β
- Heat shock proteins
What are the proteins encoded in the class I region of the MHC genome? Are they highly conserved?
The class I-like proteins are highly conserved. They include:
- HLA-E: NK cell recognition -HLA-F: Localized to endoplasmic reticulum and Golgi apparatus
- HLA-G: On fetal-derived placental cells
- HLA-H: Involved in iron metabolism
