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ABAI > Ch 1 - immune mechanisms > Flashcards

Ch 1 - immune mechanisms Flashcards

1
Q

What is interferon (IFN)?

A

a. IFN is a type of protein / cytokine / molecule used for communication b/w cells to trigger protective defense mechanisms from the immune system to help eradicate pathogens
b. Interferons are named for their ability to “interfere” with viral replication by protecting cells from viral / bacterial infections (or possibly tumors)

The immune system uses pattern recognition (TLR/ RIG) receptors to look for unique molecules from microbes…which leads to production / release of IFN

  • viral glycoproteins
  • viral RNA
  • bacterial endotoxin (lipopolysaccharide)
  • bacterial flagella
  • CpG motifs

c. IFNs have various other functions:

  • they activate immune cells, such as natural killer cells and macrophages
  • they increase consumption and subsequent presentation of antigen by the MHC molecules to the T-cells
  • can cause symptoms such as fever, muscle pain and “flu-like symptoms” as a consequence of infection by production of IFNs and other cytokines
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2
Q

What are the diffrent types of IFN?

A

There are a few different types of IFN:

In general, type I interferons are produced when the body recognizes a virus that has invaded it

Type I interferons include:

  • IFN-α,
  • IFN-β
  • IFN-ε, IFN-κ, IFN-ω

Type II interferon is:

  • IFN-γ

IFN-y blocks production of type-2 T helper cells (Th2)

  • This decrease in Th2 immune response leads to a further induction of Th1 immune response – but also decreases the “allergy response” – IL-4 / IL-13 / IL-5
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3
Q

What cells make IFN?

A

IFN-α​ & IFN-B (Type I INF) are produced by:

  • Fibroblasts
  • Monocytes

Production of IFN-α is inhibited by Interleukin-10 (IL-10)

  • T-reg cells (CD4+/CD25+ Th cells) make = IL-10
  • T-reg cells work to calm down the immune response

IFN-y (type II interferon) is made by:

  • NK cells
  • CD8 T-cells (cytotoxic T cells)
  • CD4 Th1 (Type-1 T helper cells)

IFN-y is activated by Interleukin-12 (IL-12)

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4
Q

What are the common superantigens and related diseases?

A

SEB and SEC cause food poisoning (SEB) staphylococcal enterotoxin B

(SEC) staphylococcal enterotoxin C

TSST and SPE-C cause toxic shock

TSST) toxic shock syndrome toxin

(SPE-C) streptococcal pyrogenic exotoxins C

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5
Q

Where do superantigens bind?

A

Superantigens bind to the:

  • Vβ region of TCRs (CDR4) and
  • outside of the peptide-binding groove on the MHC molecule
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6
Q

What are conjugated vaccines?

What are examples of conjugated vaccines?

A

Conjugated vaccines:

  • 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
  • meningococcal vaccines (MCV4–Menactra and Menveo)
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7
Q

Which type of T cells recognizes lipid antigens?

What is the molecule involved in recognition of the lipid?

A

Natural killer T (NKT) cells recognize lipid Ag’s

CD1 molecule present lipids to NKT cells

  • CD1 molecules activate a group of T cells, known as Natural killer T cells because of their expression of NK surface markers such as CD161
  • Natural Killer T (NKT) cells are activated by CD1d-presented antigens, and rapidly produce Th1 and Th2 cytokines, typically represented by interferon-gamma and IL-4 production
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8
Q

Where do CD8 & CD4 T-cells bind MHC class I and class II molecules, respectively?

Are the binding sites polymorphic or non-polymorphic?

A

MHC class 1 = CD8

α3 portion binds CD8

MHC class 2 = CD4

β2 portion binds CD4

Non-polymorphic

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9
Q

In humans, what are the genes contained within the MHC are called?

A

the human leukocyte antigen (HLA) genes

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10
Q

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

A

α chain (α1, α2, α3)

β2-microglobulin

Peptides (Ag) loaded onto MHC 1 is derived from:

  • Cytoplasm viral or tumor cell
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11
Q

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

A

Two alpha & two beta chains

α chain (α1, α2)

β chain (β1, β2)

Peptide (Ag) loaded onto MHC 2 is derived from:

  • Endocytose extracellular pathogen degraded by lysosome
  • Elicit macrophage activation and B cell help
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12
Q

What are the MHC class 1 peptide binding sites?

Are they polymorphic or non-polymorphic?

A

α1 and α2 (polymorphic)

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13
Q

What are the MHC class 1 genes?

A

HLA A, B, and C

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14
Q

What are the MHC class 2 genes?

A

HLA- DP, DQ, DR

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15
Q

What are the MHC class 2 peptide binding sites?

Are they polymorphic or non-polymorphic?

A

α1 and β1 (polymorphic)

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16
Q

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

A

Peptides with 8–11 amino acids

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17
Q

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

A

Peptides with 10–30 amino acids

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18
Q

Where does antigen sampling occur for MHC class 1 cells (intracellular or extracellular)?

A

Intracellular – interacts with CD8 T-cells

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19
Q

Where does antigen sampling for MHC class 2 cells occur (intracellular or extracellular)?

A

Extracellular – interact with CD4 T-cells

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20
Q

Which cells express MHC class 2?

A

APC’s

  • dendritic cells
  • macrophages
  • B lymphocytes

** Also Thymic Epithelia and activated T-cells

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21
Q

What cytokines induce production of MHC class 1 cells?

A

Interferon

  • IFNα
  • IFNβ
  • IFNγ
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22
Q

What cytokines induce production of MHC class 2 cells?

A

IFNγ

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23
Q

What are the major steps in the MHC 1 antigen 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
  • The antigenic peptides are then transported into the endoplasmic reticulum by transporter of antigenic-processing (TAP) proteins.
  • Tap proteins are composed of two subunits:
  • TAP1 and TAP2
  • both of which must be present for function
  • The antigenic peptides are loaded onto newly synthesized MHC class I polypeptides, and transported to cell surface
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24
Q

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

A

From interaction with calnexin, calreticulin, Erp57, and tapasin

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25
Q

Can any viruses evade MHC class 1 presentation?

A

Herpes simplex virus (HSV)

  • can block TAP transportation

Cytomegalovirus (CMV)

  • can remove MHC class I molecule from ER
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26
Q

What type of antigens do MHC class I molecule presents to CD8 cells?

Where does the antigen-MHC class I loading take place?

A

Intracellular antigens

(e.g., viral antigen in cytoplasm)

The loading site occurs in endoplasmic reticulum (ER)

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27
Q

What are the major steps in the MHC 2 antigen presentation pathway?

A

MHC II Pathway
-Extracellular antigen (microbe) is endocytosed and compartmentalized in cytosolic phagosomes, then degraded the microbe into antigenic peptides by proteases (cathepsins)

  • The 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 the antigenic peptides to be loaded in the MHC-binding cleft
  • MHC class II and peptide are transported to cell surface
28
Q

Why does the Invariant chain (Ii) block the binding groove on the MHC II molecule in the ER?

A

To prevent loading by peptides destined for class I molecules

CLIP (Class II- associated invariant chain peptide) uses proteases to degrade the invariant chain so that the MHC class II selected antigen (peptide) can be loaded up for presentation to a CD4 T-cell

29
Q

What is HLA-DM?

Where is it located?

What is its function?

A

HLA-DM

  • Claim to fame = removes CLIP and allows antigenic peptides to be loaded in the MHC-binding cleft

HLA-DM is an intracellular protein involved in MHC class II antigen processing. It does not present antigenic peptides nor is it a component of MHC class II

30
Q

What is bare lymphocyte syndrome?

A

Rare recessive genetic condition in which the major histocompatibility complex class I or II are not expressed

Clinically similar to SCID, however, bare lymphocyte syndrome does not result in decreased B- and T-cell counts – as the development of these cells is not impaired

MHC class 1 deficiency = TAP (transporter associated with antigen presentation) deficiency

  • Sinopulmonary infections
  • granulomatous skin lesions
  • necrobiosis lipoidica

MHC class 2 deficiency = no CD4 T-cell function (even though the CD4 T-cell is present…nothing is presenting Ag to it)

  • mutations in genes that code for proteins (transcription factors) that would normally regulate the expression MHC II genes
  • Diarrhea
  • hepatosplenomegaly
  • transaminitis
  • sclerosing cholangitis (Cryptosporidium parvum)
  • pulmonary infections (Pneumocystis jiroveci, encapsulated bacteria, Herpesviridae, and RSV)
  • meningitis
31
Q

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

A

MHC class 1 deficiency:

  • CD8 lymphopenia
  • PBMC on flow cytometry lack MHC class 1

Tx = Treat pulmonary infections like CF (aggressive toileting and chest PT)

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

Tx = Hematopoietic stem cell transplantation (HSCT)

32
Q

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

A

High concentration and high affinity promote negative selection.

33
Q

What three fates can occur in central B-lymphocyte tolerance?

A

When the precursor B lymphocyte is exposed to a self-antigen in the bone marrow during development, three possible fates arise:

  • apoptosis (negative selection)
  • receptor editing
  • anergy
34
Q

What is receptor editing?

Which type of tolerance does this occur in?

A

Receptor editing involves re-activation of RAG1 and RAG2 after 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, allowing the self-reactive immature B cell to 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.

35
Q

What two factors cause anergy in peripheral T-lymphocyte tolerance?

Name 4 ways anergy is maintained.

A

2 Factors for peripheral T-cell anergy:

  • Lack of a second signal
  • Lack of innate costimulation (eg. microenvironment).

T-cell anergy can be 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 that present self-antigen without expression of costimulatory molecules

36
Q

As T-lymphoctes develop in the thymus, their binding affinity with MHC or self-peptides will determine what they will become.

What will happen to T-cells with:

  • weak binding
  • intermediate binding
  • strong binding
A
  • Weak binding - positive selection (effector cells)
  • Intermediate binding - Treg
  • Strong binding - apoptosis (negative selection)
37
Q

Which chains (heavy or light) are rearranged in B-cell receptor editing?

In what order does this occur?

A
  • κ light chains are rearranged first
  • If receptor editing is needed, a λ light chain will be used
38
Q

What do surface molecules do Tregs express?

A

T-regs express:

  • CD4
  • CD25 (IL-2R alpha chain)
  • FOX P3
39
Q

What cytokines does T-reg cell survival depend on?

A

IL-2 and TGFB

40
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.

41
Q

What do FoxP3 mutations cause?

A

FoxP3 mutation in human cause:

  • Immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome
  • Fatal autoimmune disorder characterized by a triad of watery diarrhea, eczema, and endocrinopathy.
42
Q

What is FasL? Where is it upregluated?

A

  • Fas-L (aka CD95L) is located on T-cells
  • interacts w/ Fas (CD95) on the same T-cell or on nearby cells
  • Downregulates immune response through the caspase system
  • FasL works to delete a self reactive T lympocyte or causes death of an activated cell
  • FasL is acts on repeatedly activated T lymphocytes
43
Q

What do mutations in Fas or caspase 10 cause?

A

Autoimmune lymphoproliferative syndrome (ALPS)

**Defect in Lymphocyte Apotosis → They dont know when to die → Accumulate in organs → lack of tolerance → autoimmune problems

3 types:

  1. Type I = FAS mutation
  2. Type Ib = FAS ligand mutation
  3. Type IIa = Caspase-10 mutation

Characterized by:

  • Autoimmunity (autoimmune cytopenias)
  • Lymphoproliferation (lymphadenopathy & splenomegaly)
  • Marked increased risk of lymphoma
  • d/t defect in lymphocyte apoptosis

Clinical Features:

  • Non-malignant Lymphadenopathy and/or splenomegaly
  • Elevated α/β double neg T-cells
  • Defective lymphocyte apoptosis
  • Autoimmune cytopenias
  • Hypergammaglobulinemia
  • Positive family history of ALPs or early lymphoma

Dx:

  • Elevated IL-10 levels
  • Elevated vitamin B12 levels
  • Soluble Fas Ligand
44
Q

What is a frameshift mutation?

A

Frameshift- Insertion or deletion causes a shift in the translational reading frame. More dramatic effect on peptide sequence.

45
Q

What is a missesne mutation?

A

Missense Mutation

  • Single-nucleotide substitution causes the translation of a different amino acid
  • This amino acid substitution may have no effect, or it may render the protein nonfunctional
46
Q

What is a nonsense mutation?

A

Nonsense Mutation

  • Single-nucleotide substitution causes an early stop (or termination) codon.
47
Q

What is a silent mutation?

A

Silent Mutation

  • Single-nucleotide substitution does not cause a change in amino acid sequence
48
Q

What is a neutral mutation?

A

Neutral Mutation:

  • Single-nucleotide substitution causes a different but similar amino acid to be translated
49
Q

What is an SNP?

A

A single-nucleotide polymorphism (SNP) is a variation in DNA sequence that occurs when a single nucleotide in a gene of an individual is different from that of other individuals

  • SNPs are not mutations
  • SNPs usually occur more frequently in noncoding DNA sequences
  • Overall, these occur at a higher frequency than mutations
  • SNPs occur in varying frequency between different geographic and ethnic groups
  • Therefore, they are useful markers of human genetic variations, which sometimes underlie different susceptibilities to diseases
50
Q

What is the protein encoded by the 17q12-21 gene?

What is the function?

What is the relevance in atopy?

A

Protein - ORMDL3
Function - Unknown
Atopy relevance - Increased risk of asthma

51
Q

What is the protein encoded by the 5q22-32 gene?

What is the function?

What is the relevance in atopy?

A

Protein - CD14

Function - Lipopolysaccharide (LPS) receptor

Atopy relevance - Both increased as well as reduced risk of asthma and atopy

52
Q

What is the protein encoded by the 3p21-22 gene?

What is the function?

What is the relevance in atopy?

A

Protein - CCR5
Function - Chemokine receptor
Atopy relevance - Protection against nonatopic asthma

53
Q

What is the protein encoded by the Xp22 gene?

What is the function?

What is the relevance in atopy?

A

Protein - TLR7 and 8

Function - Pattern recognition receptor for viral ssRNA

Atopy relevance -
Increased risk for asthma, rhinitis, atopic dermatitis, and increased specific IgE

54
Q

What is the protein encoded by the 5q31 gene?

What is the function?

What is the relevance in atopy?

A

Protein - IL-13

Function - Cytokine that induces IgE secretion, mucus production, and collagen synthesis

Atopy relevance - Increased risk of asthma, bronchial hyper-responsiveness, and skin-test responsiveness. Linked to response to montelukast

55
Q

What is the protein encoded by the ADRB2 gene?

What is the function?

What is the relevance in atopy?

A

Protein - B2 -adrenergic receptor

Function - adrenaline and nonadrenaline receptor

Atopy relevance - Arg/Arg phenotype with decreased albuterol response compared with Gly/Gly phenotype at residue 16

56
Q

What is the protein encoded by the ADAM33 gene?

What is the function?

What is the relevance in atopy?

A

Protein - Type 1 transmembrane protein

Function - Involved in cell-to-cell interactions

Atopy relevance - Increased risk of asthma and bronchial hyperresponsiveness

57
Q

What are 2 genetic mechanisms that cause epigenetic changes?

A

DNA methylation and histone modification

58
Q

What is the outcome of TCR binding peptide-MHC complex (p-MHC)?

A

clonal expansion and differentiation to memory and effector stage (adaptive immune response)

59
Q

What is somatic recombination?

A

random formation of the Ag-recognition portion of the TCR

60
Q

What is selection?

A

identification of clones that both recognize potential pathogenic peptides and avoid overt self-recognition

61
Q

What is multiple alleles (polymorphism)?

A

diversify the MHC b/w individuals (thousands of alleles for each of the 6 HLA genes)

→ diff people bind diff peptides → species survival

62
Q

What are the 2 stages of clonal selection process in thymus?

A
  1. Positive selection
  2. Negative selection
63
Q

What is positive selection?

A

TCR with low affinity to self peptides present on MHC are selected against

64
Q

What is negative selection?

A

TCR with high affinity to self are eliminated

selection for tolerance, and against self reaction/immunity

65
Q

T-cells recognize both the peptide (Ag) being present – and – the MHC molecule presenting it.

Do T-cell responses differ b/w two unrelated individuals (with different MHC genes) when exposed to or infected with the same virus?

A

a. T-cells see both the peptide (Ag) and the MHC molecule that is presenting the peptide to the TCR.
b. If T-cells for a particular peptide (Ag) where transplanted from another individual, they would be specific to a particular MHC molecule from the donated person.
* Therefore, the donated T-cell may be able to recognize the peptide (Ag) – but would not be able to recognize the MHC molecule that it was being presented by
c. T-cells which match a particular MHC and peptide combination would not be able to bind the same MHC molecule if it was binding a different peptide (Ag)

66
Q

What determines whether an autoimmune disease occurs?

A

Certain HLA alleles/haplotypes that present particular self-peptides

Only individuals with autoimmune disposing HLA alleles/haplotypes are at risk of autoimmune disorders

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