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Allergy and Immunology > First Aid, Chapter 1 Immune mechanism: antigens, MHC, and Tolerance > Flashcards

First Aid, Chapter 1 Immune mechanism: antigens, MHC, and Tolerance Flashcards

1
Q

What is the hapten- carrier effect?

A

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.

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2
Q

What are the common superantigens and related diseases?

A

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.)

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3
Q

Where do superantigens bind?

A

Superantigens bind the Vβ region of TCRs (CDR4) and outside of the peptide-binding groove on the MHC molecule.

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4
Q

Describe how conjugated vaccines work and give some examples.

A

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).

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5
Q

Which type of T cells recognizes lipid antigens and what is the molecule involved?

A

Natural killer T (NKT) cells and CD1 molecule.

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6
Q

What are the binding sites for TCR on MHC class I and class II molecules, respectively? Are the binding sites polymorphic or non-polymorphic?

A

α3 binds CD8 and β2 binds CD4. Non-polymorphic.

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7
Q

What are the MHC class 1 genes?

A

HLA A, B, and C.

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8
Q

What are the MHC class 2 genes?

A

HLA- DP, DQ, DR.

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9
Q

What are the MHC class 1 polypeptide chains (domains)?

A

α chain (α1, α2, α3) β2-microglobulin.

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10
Q

What are the MHC class 2 polypeptide chains (domains)?

A

α chain (α1, α2) β chain (β1, β2).

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11
Q

What are the MHC class 1 peptide binding site and are they polymorphic or non-polymorphic?

A

α1 and α2 (polymorphic).

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12
Q

What are the MHC class 2 peptide binding site and are they polymorphic or non-polymorphic?

A

α1 and β1 (polymorphic).

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13
Q

How many amino acids go in the peptide binding cleft for MHC class 1?

A

Peptides 8–11 amino acids.

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14
Q

How many amino acids go in the peptide binding cleft for MHC class 2?

A

Peptides 10–30 amino acids.

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15
Q

Is the antigen sampling for MHC class 1 intracellular or extracellular?

A

Intracellular.

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16
Q

Is the antigen sampling for MHC class 2 intracellular or extracellular?

A

Extracellular.

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17
Q

Which cells express MHC class 1?

A

Most nucleated cells.

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18
Q

Which cells express MHC class 2?

A

APC (dendritic cells, macrophages, and B lymphocytes), thymic epithelia, and activated T lymphocytes.

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19
Q

What are the inducing cytokines for MHC class 1?

A

Interferon (IFN)α, IFNβ, and IFNγ.

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20
Q

What are the inducing cytokines for MHC class 2?

A

IFNγ.

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21
Q

Describe the MHC 1 presentation pathway.

A

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.

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22
Q

How to MHC class 1 polypeptides remain sequestered in the endoplasmic reticulum?

A

interacting with calnexin, calreticulin, Erp57, and tapasin.

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23
Q

How are cytoplasmic proteins degraded in the MHC class 1 pathway?

A

Cytoplasmic proteins that enter the cytoplasm are degraded to antigenic peptides by the proteasome.

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24
Q

How are antigenic peptides transported into the endoplasmic reticulum in the MHC class 1 pathway?

A

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.

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25
Q

Name 2 viruses that evade MHC class 1 presentation and describe how.

A

Herpes simplex virus (HSV) can block TAP transportation, and cytomegalovirus (CMV) can remove MHC class I molecule from ER.

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26
Q

MHC class I molecule presents which type of antigens and where does the antigen-MHC class I loading happen?

A

Intracellular antigens (e.g., viral antigen in cytoplasm) and the loading site is endoplasmic reticulum (ER).

27
Q

Describe the MHC II presentation pathway.

A 
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.
28
Q

What is HLA-DM? Where is it located? What is its function?

A

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.

29
Q

What is the invariant chain (li) and where is it located? What happens to it and what does it become?

A 
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.
30
Q

What are the bare lymphocyte syndrome defects? What are the mutations in them? What is the inheritance?

A 
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.
31
Q

What are the clinical features of the bare lymphocyte syndromes?

A

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

32
Q

What are the lab findings of the MHC class 1 and 2 deficiencies?

A

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

33
Q

What is the treatment for MHC class 1 and 2 deficiencies?

A

MHC class 1 deficiency: Treat pulmonary infections like CF (aggressive toileting and chest PT)

MHC class 2 deficiency: Hematopoietic stem cell transplantation (HSCT)

34
Q

MHC class II molecule presents which type of antigens and where does the antigen-MHC class II loading happen?

A

Extracellular antigens (e.g., antigens from phagocytosed bacteria) and loading site is phagolysosome.

35
Q

What is autoimmune polyglandular syndrome and what gene is mutated in it?

A

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.

36
Q

Describe central T-Lymphocyte Tolerance.

A

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.

37
Q

What factors promote negative selection in central T-lymphocyte Tolerance?

A

High concentration and high affinity promote negative selection.

38
Q

What does the autoimmune regulatry gene (AIRE) do?

A

The autoimmune regulatory gene (AIRE) is expressed in the thymus. This gene promotes expression of nonthymic tissue antigens in the thymus.

39
Q

Describe central B-lymphocyte tolerance.

A

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

40
Q

Describe receptor editing, which type of tolerance does this occur in?

A

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.

41
Q

In peripheral T-lymphocyte tolerance, what are the possible fates?

A

Anergy, deletion, or regulation.

42
Q

What two factors cause anergy in peripheral T-lymphocyte tolerance? Name 4 ways anergy is maintained.

A

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.

43
Q

Describe how dendritic cells maintain anergy.

A

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.

44
Q

What types of t-lymphoctes develop in the thymus with weak, intermediate, and strong binding between the cells and self-peptide/MHC complex respectively.

A

Weak binding - positive selection (effector cells)
Intermediate binding - Treg
Strong binding - apoptosis (negative selection)

45
Q

What is the result of lack of costimulation or lack of an innate system response with respect to T-lymphoctyes?

A

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.

46
Q

What chains are rearranged in B cell receptor editing and in what order?

A

κ light chains are rearranged first. If receptor editing is needed, a λ light chain will be used.

47
Q

What do Tregs express?

A

CD4, CD25 (IL-2R alpha chain), and FOX P3.

48
Q

What cytokines do Tregs survival depend on?

A

IL-2 and TGFB.

49
Q

What cytokines maintain tolerance or regulation of Tregs? And what cells do the cytokines target?

A

IL-10 and TGFB. IL-10 targets macrophages and dendritic cells and TGFB inhibits lymphocytes and macrophages.

50
Q

What is Bim? How is it activated?

A

A propaptotic member of the Bcl-2 protein family. Activated by T-lymphocytes that repeatedly recognize self-antigens without costimulation.

51
Q

What pathway does Bim cause apoptosis through?

A

Mitochondrial pathway.

52
Q

What is the CD name for FasL?

A

CD95L

53
Q

Where is FasL located?

A

On the T lymphocyte.

54
Q

Where is FasL upregluated? What does it do?

A

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.

55
Q

What system does Fas: FasL signal through?

A

Caspase system.

56
Q

What do FoxP3 mutations cause? Describe it?

A

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.

57
Q

What do mutations in Fas or caspase 10 cause?

A

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.

58
Q

Why are B cells not activated without the help of Tcells?

A

Antigens cannot cross-link the BCR on their own, so B cells become anergic or are induced to apoptosis.

59
Q

What is downregulated with chronic antigen recognition that inhibits B-lymphocyte honming and interaction with T lymphyocytes? What is the end result?

A

CXCR5 is downregulated, yields B cell apoptosis.

60
Q

What chromosome are genes that encode MHC located on? On what arm? Where is the B2 microglobulin chain encoded?

A

Genes that encode MHC molecules are encoded on the short arm of chromosome 6, whereas the β2-microglobulin chain is encoded on chromosome 15.

61
Q

What else does the MHC genome encode in addition to MHC polypeptides?

A

In addition to encoding the MHC polypeptides, the MHC genome encodes proteins involved in the processing of peptides that occupy the peptide-binding clefts.

62
Q

What does the class III region of the MHC genome encode?

A
  • 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
63
Q

What are the proteins encoded in the class I region of the MHC genome? Are they highly conserved?

A

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

Allergy and Immunology (68 decks)

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