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Immunology > MHC Antigen > Flashcards

MHC Antigen Flashcards

1
Q

Any antigen that defines an immunogenic distinction between 2 non-identical individuals of the same species can be called an ________.

A

-allo-antigen

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2
Q

Different categories of histocompatibility antigens

A
  1. Minor: antigens that elicit histo-incompatibility that are slow and weak responses relative to MHC
  2. Major (MHC): cell surface proteins encoded within a set of tightly linked genes that elicits huge immune rejection of transplants
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3
Q

What does the MHC encode and what do they react with in recipient tissue?

A
  • cell surface proteins

- elicit immune responses by host T cells

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4
Q

MHC alleles define “self” and are expressed in a ________ fashion.

A

-co-dominant

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5
Q

How (generally speaking) are the antigen receptors on T and B cells similar?

A
  • both T and B cells express many copies of only 1 type of antigen receptor on their surface; therefore, each T or B cell can respond to only a single antigen specificity
  • once stimulated to respond, both T and B cells clonally expand to combat the antigen, but each cell still have reactivity against only a single antigen
  • antigen reactivity of the R comes from random rearrangements of various gene segments
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6
Q

What is one HUGE difference in what T and B cell R respond to?

A

-B cells respond to soluble antigen, whereas T cells respond only to antigen found on the surface of other cells

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7
Q

T cell responses are “MHC restricted”. What does the T cell bind to on the MHC?

A

-both the MHC molecule and the peptide it is presenting

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8
Q

What is the advantage of having such a complex system of MHC restriction and T cells?

A
  • some pathogens escape neutralizing antibodies and survive inside host cells (viral and bacterial)
  • thus, humoral mediation will not do, and the MHC system offers cell-mediated processes to solve these infections
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9
Q

What is the role of Cytotoxic T lymphocytes (CTLs)? What does this require?

A
  • recognize and kill the virally infected host cell before virus is released
  • requires the CTL recognize a unique peptide encoded by the viral genome and presented by the host cell MHC
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10
Q

When the pathogen is an intracellular bacterium, not virus, what T cells recognize this?

A
  • Helper T cells

- initiate inflammatory response which at lease contains and may even kill bacteria before infection spreads

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11
Q

What are the effector activities of Th cells?

A
  • initiate activation of CTLs to kill infected target cells
  • stimulate B cells to secrete more and better antibody
  • activate macrophages and granulocytes to mediate an inflammatory response
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12
Q

Name the 2 classes of MHC proteins and the cells which express them, and who they present to.

A

1) MHC Class I: all nucleated cells express this and present antigen to CTLs (CD8+ cells); usually these antigens ceom from proteins made by cell itself
2) MHC Class II: professional APCs (also have MHC Class I); capture exogenous antigen and present to helper or CD4+ T cells using class II mlcs

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13
Q

What cells can function as APCs? Therefore, what must these cells all express?

A
  • Macrophages: cell lineage that populates nearly all tissues; derived from circulating monocytes and function as phagocytes; critical for ingesting microbes
  • Dendritic cells (DCs): MOST efficient APCs; present in many tissues usually in immature form that can capture antigen; following maturation, these cells “present” antigen to T cells in secondary lymphoid tissue
  • B cells: capture soluble antigen when it binds to surface Ig; antigen is internalized and can then be presented by class II MHC to T cells

** all have MHC II in addition to MHC I

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14
Q

Which is the best APC?

A

-DC cells

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15
Q

Where do APCs capture antigens?

A
  • lymph node/tissue found APCs capture antigen from epithelium and CT
  • blood-borne antigens are captured by APCs in the spleen
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16
Q

DC cells are found in nearly all _______ surfaces. Describe their maturation process.

A
  • epithelial surfaces (EX. Langerhans cells in skin) and LN
  • Most tissue DCs are immature, able to capture antigen, but not very capable of presenting antigen to T cells; As they capture antigen, they are stimulated by pathogen products and inflammatory cytokines to mature, becoming more efficient at antigen presentation to T cells
  • DCs then travel to secondary lymphoid organs where they encounter antigen-specific T cells and initiate response
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17
Q

Where are the DCs found within LNs?

A

-T cell zone (cortex)

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18
Q

What changes occur in a DC as it matures?

A
  • DCs become less adherent to epithelium and begin to migrate to secondary lymphoid tissues
  • upregulate expression of molecules critical for T cell activation like MHCII and co-stimulatory ligands
  • Inflammatory cytokines upregulate R on DCs that make them sensitive to chemokines that lead them to LNs
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19
Q

T/F: APCs only present antigen to CD4+ Th Cells.

A
  • False; they also have MHC Class I (as do all nucleated cells) and can thus present to CTLs too
  • *Cross presentation**
  • technically present to naive CD8+ cells which then form CTLs
  • important for viral infections
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20
Q

Where do professional APCs engulf antigen and then present?

A
  • engulf in periphery

- present that antigen to T cells in secondary lymphoid organs

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21
Q

The T cell receptor binds AA from what?

A
  • both the antigen and MHC

- T cells see a composite structure composed of a peptide derived from a foreign antigen and self MHC molecule

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22
Q

MHC molecules are both ______ and ________.

A
  • polygenic
  • polymorphic
  • many MHC genes, each with many alleles=diversity
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23
Q

MHC molecules present peptides arising from both foreign (non-self antigens) and self-antigen. Ideally, what should happen?

A
  • T cells should respond to only non-self peptides in a self MHC molecule
  • this is achieved through T cell selection in thymus and peripheral tolerance
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24
Q

Both classes of MHC molecules display peptides on the surface of the cell, allowing T cells to recognize the foreign materials. Describe the type of peptides displayed by type II and type I MHC molecules.

A
  • Class II MHC: generally derived from ingested material

- Class I MHC: endogenously synthesized proteins (think virus)

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25
Q

There are other MHC-like molecules ( one example is ______) that present _______ to unique populations of lymphocytes.

A
  • CD1

- non-peptide antigens like lipids

26
Q

MHC residues that bind the TCR are polymorphic, meaning that these regions of the MHC molecules vary widely from person to person in the population. What does this imply?

A

-TCR from one person will bind self MHC, but not nonself MHC molecules

27
Q

Structure of MHC Class I molecules

A
  • single polymorphic heavy (alpha) chain and a non-MHC encoded, non-polymorphic light chain (B2-microglobulin B2m)
  • multiple gene loci in all mammals: HLA-A,B,C in humans
  • Heavy chain: 3 extracellular domains (a1,a2,a3), an integral membrane domain that spans bilayer, and short C terminal cytoplasmic domain; a1 and a2 make peptide binding cleft; a3 and b2m are stabilized by disulfide bonds that form platform upon whih a2 and a2 sit
28
Q

Who expresses MHC Class I and what to they present and to who?

A
  • present peptides to CTLs (CD8+ T cells)

- expressed on all nuclear cells in the body

29
Q

What do MHC class II molecules present, to who? What can they be induced by?

A
  • present peptides to helper T cells (CD4+)
  • expressed by limited number of cell types (DCs, macrophages, B cells, thymic epithelia)
  • induced in other cell types by IFNy or TNF
30
Q

Structure of MHC class II molecules

A
  • 2 polymorphic heterodimer MHC-encoded chains, a and b
  • each chain has 2 extracellular domains (a1,a2,b1,b2), a single integral membrane domain spanning bilayer, and short C terminal cytoplasmic domain
  • a1 abd b1 make peptide binding cleft; a2, b2 stabilized by disulfide bonds and form platform upon which a1, b1 sits
  • Multiple gene loci in all species: HLA-DR, DQ, DP in humans
31
Q

The MHC complex (of class I and class II) is designated _____ in human. The genes are clustered together on chromosome 6. They are inherited together.

A

-HLA

32
Q

Name the 3 major classes of Type I and Type II MHC

A

Type I: A, B, C
Type II: DP, DQ, DR
-many alleles for each gene

33
Q

Most individuals express _____ different MHC class I molecules and ______ different MHC class II molecules.

A
  • 6; 6

- 3 from each parent (1 of each class)

34
Q

Due to little crossing over within the MHC locus, offspring tend to inherit the entire maternal or paternal cluster of MHC genes; these clusters are known as _______.

A

-MHC haplotype

35
Q

Peptides fit into the _____ of MHC class I and MHC class II.

A

-groove; this peptide binding pocket is where polymorphisms exist

36
Q

_________ are stimulated by antigen in the groove of MHC class II; ________ are stimulated by antigen in the groove of MHC class I.

A
  • CD4+ Helper T cells

- CD8+ cytolytic T cells

37
Q

What 3 things do MHC class I molecules bind? What about for MHC class II?

A
  • Class I: peptide, TCR, CD8

- Class II: peptide, TCR, CD4

38
Q

CD8+ T cells respond to antigens from ______ produced proteins. CD4+ T cells respond to antigens from ______ produced proteins

A
  • endogenously

- exogenously

39
Q

Why is it beneficial to have co-dominant expression of MHC molecules?

A

-this essentially doubles the number of possible antigens that any individual’s MHC molecules can potentially present to T cells

40
Q

What is the end result of having highly polymorphic MHC genes?

A

-ensures that different individuals are able to present and respond to different microbial peptides

41
Q

Do MHC molecules or T cells distinguish between self and nonself?

A
  • T cells

- MHC molecules sample everything, it is up to the tolerance of a T cell to decide whether or not to respond

42
Q

Do MHCs have narrow or broad specificity?

A

-broad: which is necessary because this allows many different peptides to bind to the same MHC molecule, but not ALL peptides can bind any MHC

43
Q

T/F: MHC’s can only display 1 peptide at a time.

A

-True

44
Q

T/F: MHC’s are expressed on the cell surface only when they are displaying peptides.

A
  • True; only MHC molecules that are displaying peptides are expressed for recognition by T cells
  • those not with peptide and very unstable on the surface and are internalized
45
Q

Why do MHC’s present self peptides?

A
  • peptides presented by MHC present all proteins encountered by the cell; there is no selectivity for foreign particles at level of MHC peptide binding
  • selectivity for immune response comes from ability of T cells to distinguish self from foreign
46
Q

What is antigen processing?

A
  • mechanism by which antigens are broken down into peptides and inserted into the binding groove of MHC molecules
  • mechanisms are different between class I and class II
47
Q

MHC class I is specialized to capture peptides from _____ proteins and MHC class II is specialized to capture peptides from the _____ system.

A
  • cytosolic

- endosomal

48
Q

MHC class I presents antigenic peptides from proteins made within the cell, including foreign and self peptides. How does this occur?

A
  • as proteins are made, portion are misfolded and becomes ubiquinated
  • these are marked for transport into proteosome where they are broken down into fragments of peptide
  • fragments transported into ER by TAPs, where they bind to newly made class I molecules and these complexes are transferred to cell surface
49
Q

Mechanism of antigen processing and presentation in MHC class II

A
  • pathogens engulfed into endosome where they are fused with lysosomes and degraded
  • meanwhile. MHC II are constantly being made in ER and associate with an invariant chain (CLIP) that will bind the groove to stabilize it until peptide fills this spot
  • Class II and invariant chain are exocytosed to surface and on the way, bind with lysosome containing peptides and switch occurs
  • *remember, self peptide can also be expressed
50
Q

Name 2 factors that facilitate switch of antigenic peptide for invariant chain in MHC class II

A
  • endosomal vesicles are acidic which favors release of CLIP

- endosomes contain DM protein which competes for invariant chain

51
Q

Different APCs are specialized in different ways for antigen uptake into the endosomal system for class ______ presentation.

A

II

52
Q

What are the 3 different ways that APCs take up antigen? Which APC does which mechanism?

A
  1. Macrophages (lesser extent DCs) internalize antigen by phagocytosis
  2. B cells: Surface Ig/BCR binds antigen and then signals activate B cell. The antigen is then internalized. degraded, and meets class II MHC where it is expressed; receptor mediated endocytosis
  3. DCs take up material non-specifically at sites of inflammation by macropinocytosis; they then migrate to the LN and spleen for presentation and to stimulate naive T cells
53
Q

Summary class I antigen presentation: what is the protein source; what is the degradation pathway; how does the MHC-peptide reach surface?

A
  1. protein source is endogenous antigen made normally by cell or viral gene product after infection
  2. cytosolic proteosome machinery samples all newly made proteins, leading to random protein degradation
  3. TAP transporters carry peptides into ER where class I MHC is being synthesized
  4. Class I binds peptide in ER and is exported to cell surface
54
Q

Summary class II antigen presentation: what is the protein source; what is the degradation pathway; how does the MHC-peptide reach surface?

A
  • exogenous antigen that is engulfed by endocytosis (B cells), phagocytosis (macrophages) or pinocytosis (DCs)
  • degraded to short peptides by proteases in endosomal compartments
  • newly made MHC II with invariant chain is transported into endosomes
  • DM competes away invariant chain, making room for endosomal peptides to bind class II
  • peptide bound class II is transported to surface
55
Q

Give 3 examples of dysfunction of class I MHC that leads to human disease

A
  1. Genetic defects: TAP deficiency results in a variant of SCID bc peptides are not available for class I to bind
  2. tumors: evade T cell responses by downregulating expression of MHC class I, B2m, or TAP
  3. Viruses: evade T cell responses by genetic down regulation or by physical interference with TAP function, MHC class I assembly, MHC class I transport
56
Q

2 examples of dysfunction of class I MHC that lead to human disease

A
  1. one SCID variant due to failed expression of MHC class II molecules called bare lymphocyte syndrome, a TF mutation
  2. some bacteria interfere with endosome to lysosome transport ad thus keep their antigens away from class II
57
Q

Give the outcome of these 3 scenarios:

  1. Mixing strain A LCMV-specific CTLs with strain A cells also infected
  2. Mixing strain A LCMV-specific CTLs with strain A cells uninfected
  3. Mixing strain A LCMV-specific CTLs wit strain B infected
A
  1. lysis; CTL recognizes foreign peptide and self MHC
  2. no lysis: failure to recognize self peptide + self MHC
  3. no lysis: failure to recognize foreign peptide + allogeneic MHC

T cells will only respond to other cells that express self MHC mlcs and also express the specific peptide antigen for which the T cell R has reactivity

58
Q

Give 3 ways that the T cells respond to non-self (allo) MHC in organ transplant

A
  1. The host T cell recognizes an allogenic MHC molecule whose structure resembles the self MHC-foreign peptide complex; regardless of the peptide in the cleft, bc the foreign MHC molecule by itself mimics self MHC + peptide
  2. the host T cell recognizes a structure formed by both the allogeneic MHC molecule and the bound peptide
  3. host cells engulg transplant cells and present their MHC molecules with the T cells recognize; indirect allorecognition
59
Q

Who are the only individuals who can be transplanted without fear of rejection?

A

-identical twins

60
Q

What does “matching” transplants for recipients mean?

A
  • looking for donors who share as many HLA alleles as possible with the recipient
  • some HLA loci are more important than others
61
Q

T/F: HLA matching ensures graft survival.

A
  • False

- there are other genetic loci, like minor histocompatibility antigens) that influence graft survival

Immunology (13 decks)

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