hypersensitivity/autoimmunity/deficiencies

Question 1

Describe the steps in Type 1 HS sensitisation (pretty long answer fyi - probably need to split this up)

Answer 1

antigen is either inhaled (very soluble) and enters mucusal respiratory lining OR ingested (degradation resistance) and resists degradation so can enter into gut endothelium

once antigen enters mucosa, DCs will do the usual process and present to CD4 T cells causing differentiation into TH2 (release IL4/5/13) accept this fact.

TH2 act similarly to Tfh and help B cells develop and isotype switch to IgE (via IL4)
(occurs in GC !!!)

Plasma B cells produce IgE which will go to mast cells and sensitise them (IgE binds to FcεRI receptors on mast cells.)

STRONGLY NOTE: The place in which mast cells are sensitised is very important because mast cells are what i like to call ‘locked in’ to their tissue

Question 2

what happens during T1HS immediate and delayed responses?

Answer 2

immediate (minutes): redness + swelling due to mast cells releasing pre-formed mediators: histamine, prostaglandins, leukotrienes (lipid mediators), cytokines

delayed (hours-days): LOTS of swelling due to lots of leukocytes (neutrophils, TH2, eosinophils)

Question 3

Describe Type 2 HS and provide 2 examples

Answer 3

auto IgM and IgG antibodies bind to self-antigen resulting in:

• activation of complement (both IgG & IgM)
• opsonisation via Fc (IgG only)
• antibody-dependent cell-mediated cytotoxicity via Fc (IgG only)

IgM’s Fc region is not recognised by mediators.

2 examples are Graves Disease and Myasthemia Gravis

Question 4

Describe the Rhesus example for T2HS

Answer 4

Autoantibody-like response against red blood cells:

If an Rh- mother is exposed to Rh+ fetal red blood cells (delivery of the first baby), she produces IgG against babies Rh+

These maternal anti-Rh IgG antibodies cross the placenta in subsequent pregnancies = destruction of fetal RBCs = not good

This triggers the classic T2HS mechanisms:

Complement activation → lysis of fetal RBCs.

Opsonization → phagocytosis of antibody-coated RBCs by fetal macrophages.

Antibody-dependent cellular cytotoxicity (ADCC) may also contribute.

Question 5

Describe T3HS

Answer 5

ANATIBODY:antigen = large immune complexes form = easily cleared by macrophages.

Issues arise when antibody:ANTIGEN. small soluble complexes which avoid phagocytosis can disposit.

accumulate can activate complement = tissue damage driven by neutrophils.

Question 6

how does activation of complement result in tissue damage?

Answer 6

Membrane Attack Complexes (MAC)

+

recruited neutrophils via inflammation release ROS + toxic granules/enzymes

Question 7

Describe T4HS (DTH)

Answer 7

sensitisation: antigen enters activates DCs, differentiation of T cells to TH1 = primed for next time

response: TH1 releases IL2, TNFa, IFNy (activates macrophages)

macrophages engulf and try and destory pathogen with TH1 activation, if it persists then morph into multi-nucleated giant cells = granuloma

CD8s are also primed and will try kill pathogen on reexposure.

Question 8

We all have auto-reactive antiobodies but there are 3 reasons why we all don’t have autoimmunity

Answer 8

antigen is not available due to antigen sequestration/immunological ignorance

abscence of co-stimulation signals results in keeping T cells anergic or tolerant even if they recognize self-antigen.

auto-reactive B cells may not have matching auto-reactive CD4 T cells to activate them

Question 9

autoimmunity requires which 3 factors to manifest

Answer 9

• genetic susceptibility
• environmental factors
• loss of self-tolerance

Question 10

Name the 3 B cell related autoimmune diseases we covered + concise summary of issue

Answer 10

Graves disease = stimulating antibodies

Myasthenia Gravis = inhibitory antibodies

Systemic lupus erythematosus = immune complex deposition

Question 11

Describe Graves disease + which type of hyersensitivity is it?

Answer 11

• TSH (from pituitary) stimulates thyroid via TSH receptor to produce TH and TH negatively feeds back on pituitary
• Antibodies bind to and stimulate the TSH receptor on thyroid stimulating TH production without negative feedback (hyperthyroidism)
• T2HS because antibodies just target our own cells

Question 12

Describe Myasthenia Gravis + which type of hyersensitivity is it?

Answer 12

• antibodies bind and block post-synaptic ACh receptors = no Na+ influx = no AP generation = weak muscles
• Additionally, complement can be activated and destroy the motor end plate (via neutrophils)
• T2HS

Question 12

Describe Systemic lupus erythematosus (SLE) + which type of hyersensitivity is it?

Answer 12

B-cells are hyper reactive producing auto-antibodies which bind free-floating DNA in the blood via IgG and also cause general immune complex deposit in the kidney.

Note both of these end up with clumping of antigen-antibody and complement activation

• environmentally driven
• females more than males

Question 13

what are the two T cell mediated autoimmune conditions we covered?

Answer 13

Muscle Sclerosis (MS) + type 1 insulin dependent diabetes mellitus (IDDM)

Question 14

Describe type 1 insulin dependent diabetes mellitus (IDDM), who is particularly at risk of getting this shi?

Answer 14

• juvenile onset
• activated CD4/8 T cells target beta-islet pancreatic insulin cells
• loss of insulin secretion = cells can’t take up glucose = elevated blod glucose
• at risk if have HLA DR3-DQ2 and DR4-DQ8 (these are MHC genes)

Question 15

Immunocompromisation vs Immunodeficient

Answer 15

Immunodeficiencies = immune system is defective completely in a particular aspect

Immunocompromised = immune system is just weakened only

Question 16

Primary vs secondary immunodeficiencies

Answer 16

Primary = inherited probably X-linked cos male only got 1 X chromosome = no redunancy/shielding from deleterious recessive alleles

Secondary = acquired via infection/cancer/chemo/autoimmunity/transplants

Question 17

easy way to diagnose immunodeficiencies

Answer 17

if they got recurrent infections probably thye got it

Question 18

3 treatment methods of immunodeficiencies + what they fix

Answer 18

intravenous immunoglobulin - fixes defect in antibody production

enzyme replacement - fixes yeah missing enzyme could be anything

bone marrow transplant - fixes SCID because both B and T cells are fricked

Question 19

Defects impacting B cell development (important ones at least)

Answer 19

ADA
IL-7Ra
RAG
BTK
AID
CD40/L
CVID

Question 20

Describe X-linked agammaglobulinemia (XLA)

Answer 20

mutation in gene coding for Btk (Bruton’s tyrosine kinase)

essential for transition between large to small pre B cell. Cell will be stuck as Large pre-B cell which only has pre-BCR with surrogate alpha chain.

Leads to apoptosis if B cell cannot mature properly = no mature B cells in periphery

No live vaccines for patient. Treat with intravenous Ig. Visible after matal Ab weaning.

Question 20

Describe hyper IgM syndrome

Answer 20

isotype switching is compromised so body can only produce IgM

3 possible genetic defects causing this:

type 1: X-linked CD40 defect
type 2: autosomal recessive AID defect
type 3: autosomeal recessive CD40 defect

Question 21

Why are individuals with hyper IgM syndromes susceptible to recurrent bacterial infections?

Answer 21

Although they can still activate complement by binding to the bacteria allowing C1 to bind them, they cannot directly opsonise because phagocytes don’t have an Fc receptor for IgM like they do for IgG/E. Direct opsonisation allows for swift killing.

Question 22

why is loss of CD40 signaling devastating for hyper IgM syndromes 1 and 3?

Answer 22

loss of CD40 signaling means no proper costimulation at the TB border between Tfh and B cells.

This means there won’t be differentiation to form the primary foci and GC = stuck with IgM descreting B cells.

ALSO it affects CD40/L interactions at within the GC between Tfh and B cells trigger isotype switching

ALSO if no CD40 interactions = no ‘testing’ of affinity maturation mutation meaning disadvantangeous mutations have a higher hance of propagating

Question 23

what does autosomal recessive inheritance describe?

Answer 23

not on a sex chromosome both parents must carry it for it to show as it is recessive

Question 24

Describe loss of AID (activation induced cytidine deaminase) enzyme

Answer 24

no initiation of isotype switching (introduces nicks into dsDNA) AND no initiation of affinity maturation (attack cytosine ring) overall just makes you stuck with IgM only

Question 25

what functions of T cells are weakened and fine as a result of hyper IgM syndromes?

Answer 25

CD4 activation and differentiation into TH1/2/17 or Tfh is fine Tfh cannot activate B cells at the TB border due to lack of CD40 signaling CD8 activation is very limited as CD40/L is required for licensing

Question 26

IgA immunodeficiency

Answer 26

IgA usually protect mucosal surface (gut and respiratory tract) we don't know the cause

Question 27

CVID (common variable immunodeficiency)

Answer 27

defect in 1+ genes affecting B cell growth or stimulation reduced IgG and IgA

Question 28

Factors impacting T cell development

Question 29

Describe DiGeorges Syndrome

Answer 29

gene deletion @ chromosome 22 which affects Tbx1 Loss of Tbx1 = failure of thymic development = defect in T cell maturation Note: this condition affects B cells as no CD4 = no activation of B cells

Question 30

Describe Bare lymphocyte syndrome

Answer 30

MHC 1/2 is gone Type 1 = MHC1 deficiency is caused by loss of TAP protein channel Type 2 = MHC2 deficiency is caused by loss of a host of enzymes

Question 31

What is the consequence of no MHC2?

Answer 31

no positive selection in thymus (applies to no MHC1 as well), less T helper cells, reduced antigen presentation

Question 32

Describe Wiskott-Aldrich syndrome

Answer 32

X-linked defect in WAS protein which causes alteration of cytoskeleton upon T cell binding to targets Altered cytoskeleton allows for good fit. WIthout this not good enough contact @ immunological synapse for effective perforin/granzyme pathway in general without cytoskeleton remodeling, T cells cannot interact properly with anything.

Question 33

Describe Familial Hemophagocytic lymphohistiocytosis

Answer 33

autosomal recessive disorder affects perforin gene, causing lack of perforin in CD8s CD8s lose their ability to kill swiftly. They have prelonged contact to keep trying and become exhausted and cause cytokine storm in process

Question 34

Describe SCID (severe combined immunodeficiency), the causes, and the treatment.

Answer 34

deficiency (complete loss essentially) in B,T, and NK cell functions caused by ADA, JAK3, RAG, or common gamma chain mutations treat with bone marrow transplant

Question 35

Why does ADA deficiency lead to SCID?

Answer 35

required for breakdown of toxic purines.

Question 36

Why does RAG deficiency lead to SCID?

Answer 36

RAG1/2 required for V(D)J recombination to generate the receptors on B and T cells

Question 37

Apart from CD8 mediated killing, what else is perforin useful for?

Answer 37

perforin is essential for the contraction of T cells following T cell expansion where T cells start killing each other with perforin/granzyme leaving only memory T cells.

Question 38

Multiple Sclerosis (MS) steps what type of hypersensitivity is it?

Answer 38

T4HS (DTH) Genetic + Environmental Factors → Myelin antigen release → APC presentation to CD4+ T cells and CD8+ cells → Th1/Th17 activation + CD8 activation → Migration to CNS → Inflammation (cytokines + macrophages) → Demyelination + neuronal damage → Clinical MS symptoms

Question 39

Describe the steps of Coeliac Disease

Answer 39

glutamine converted to glutamic acid (-ve) via tTg glutamic acid activates DCs which process and present it on HLA-DQ2/8 CD4s TCR recognises this and are primed to TH1 via IL12/CD28.80/86 TH1 releases IL2, TNFa, and IFNy - activates macrophages > chronic inflammation > neutrophil recruitment > jejenum damage