Immunology basics Flashcards
What is immunodeficiency?
Immunodeficiency is when the immune system is unable to defend the body from micropathogens.
When the thyroid tissue is subject to an autoimmune attack, what is it called?
Thyroiditis
When the RBCs are subject to an autoimmune attack, what is the term?
Autoimmune haemolytic anaemia
When the joints are subject to an autoimmune attack, what is the term?
Rheumatoid arthritis
What system do the most common autoimmune conditions affect?
Musculoskeletal
Give 2 examples of autoimmune connective tissue diseases.
Rheumatoid arthritis
Systemic Lupus erythematous
Important tests for connective tissue disease?
Rheumatoid factor (found in 80% of those with rheumatoid arthritis) Antinuclear antibodies (SLE) WCC, ESR, CRP may also be helpful. Creatine kinase may be raised in polymyositis and dermatomyositis.
How is immunodeficiency demonstrated in the laboratory?
Reduced levels/ absence of antibodies.
What is clinical allergy?
Interaction of allergens with IgE on basophils causing the release of histamines, creating allergy sx.
How can you investigate allergy?
Allergen specific IgE testing.
What is hypersensitivity?
An over-reactive response to a stimulus/ allergen. Present in 10% population.
What are the 3 phases of immune response to a transplanted graft?
Phase 1: recognition of foreign antigens
Phase 2: Activation of antigen specific lymphocytes
Phase 3: Effector phase of graft rejection
What are the most relevant protein variations in clinical transplantation?
1) ABO blood group - can transplant between incompatible people though - as can remove Ab against A or B
2) HLA (human leukocyte antigens)
Some other determinants are also important such as minor histocompatibility genes
What are the 2 main components in transplant rejection?
1) T cell-mediated rejection
2) Antibody-mediated rejection
What cells express HLA class 1 (A,B,C)?
All cells
What cells express HLA class 2 (DR, DQ, DP)?
APCs, can be upregulated in other cells under stress
What does this picture show?
MHC class 1
What does a 2:1:0 mismatch mean in organ transplantation?
This is a type of tissue typing investigation done before a transplant to look at the difference between the patient and donor HLA molecules. It looks specifically at the HLA-A, B and DR locuses of each person.
It shows that there are 2 mismatches at the HLA-A locus, 1 mismatch at the HLA-B locus and 0 mismatches at the HLA-DR locus. This means there is a total mismatch of 3 out of a possible total of 6. This means that there is a medium risk of rejection in this patient as some locuses match, but others don’t, so the patient may recognise the donor’s tissue as foreign and reject it (mount an immune response against it).
What is the gold-standard for tissue typing now-a-days?
PCR-based DNA sequence analysis for all HLA alleles (i.e. not just A, B and DR) to determine the individual’s genotype and then compare the donor and patient HLA alleles to determine mismatches.
What does this picture show?
Graft biopsy of acute T cell mediated rejection
Shows interstitial inflammation and tubulitis (tubules have also been infiltrated by T cells)
What does this picture show?
T cell mediated acute graft rejection
Arteritis
Invasion of arterial wall with T cells
How do mycophenolate mofetil and azathioprine work in transplant patients?
Work downstream of mTOR activation - preventing T cell cycle (proliferation - Azathioprine) and Nucelotide synthesis (Mycophenolate mofetil).
How does Alemtuzumab work in tranplant patients?
Anti-CD52 - depletes T cells in transplant patients. Reducing strength and longevity of T cell reaction.
What are the 3 phases of antibody-mediated rejection of transplants?
1) B cells recognise foreign HLA
2) Proliferation and maturation of B cells with anti0HLA Ab production
3) Effector phase - Ab bind to graft endotheliu -> intra-vascular disease
What does this picture show?
Ab-mediated kidney transplant rejection
Inflammatory cells within the lumens of the capillary loops (GLOMERULITIS)
Purely vascular
Cells have been recruited by Ab laid down on the vascular endothelium
In the capillaries between the tubules this also happens (see on left) - we call this capiliritis.
Apart from inflammation, what would also stain positive in a sample of graft that the recipient had rejected via Ab mediated transplant rejection?
Complement fragments such as C4d would stain positive on vascular endothelium of the graft.
Other than rejection what other things do we see in transplant patient’s biopsies?
Drug toxicity i.e. calcineurin toxicity - tx: reduce immunosuppressive drugs (may also present with increased creatinine)
Viral infections i.e. latent infections Poliomavirus, BK nephropathy tx: reduce immunosuppressive drugs
Vascular disease small lumen and larger arterial wall - collagen and elastin - HTN and drug-induced - tx: BP control and vascular stent may be neeeded if larger arteries are affected
Post transplant lymphoproliferative disease - tx: reduce immunosuppressive drugs +/- chemotherapy
Recurrent glomerulonephritis/ issues that they had before depends on the nature of the problem
The most imporant antigenic determinant for rejection in current clinical practice of kidney transplantation is…
HLA/MHC
The main effector cells in T-cell mediated transplant rejection are…
T cells and monocyte/macrophages
A patient has an episode of acute T-cell mediated rejection 2 months post transplantation. What additional drug would most commonly be administered?
Methylprednisolone (CORTICOSTEROID) - 3 pulses given given 3 days in a row followed by an oral steroid taper.
Which cell is injured in the effector phase of Ab-mediated rejection?
Vascular endothelial cells
What is SCID?
Severe combined ImmunoDeficiency affecting multiple aspects of the immune response
What are the characteristics of CD8+ T cells?
Specialised cytotoxic cells
Recognise peptides derived from intracellular proteins in association with HLA class 1 - HLA-A, HLA-B, HLA-C
Kill cells directly (perforin, granzymes, fas-ligand)
Secrete cytokines i.e. IFN-y and TNFa
Particularly important in defence against viral infections and tumours
What clinical features might you see in a patient with Di George’s syndrome?
High forehead
Low set, abnormally folded ears, cleft palate, small mouth and jaw
Hypocalcaemia
Oesophageal atresia
Under developed thymus
Thyroid abnormalities
Complex congenital heart disease
A 1 year old boy has recurrent bacterial infections. His CD4 and CD8 T cells are present. B cells are absent
X-linked agammaglobulinaemia
Severe recurrent infections from 3 months. T cells are absent, B cells are present. Igs are low. No NK cells. Normal facial features. Normal cardiac echo.
Which is most likely?
a) 22q11.2 deletion syndrome
b) Bare lymphocyte syndrome type 2
c) X-linked SCID
d) IFN-y receptor deficiency
c) X-linked SCID
Recurrent childhood infections. Abnormal facial features, congenital heart disease. Normal B cells. REduced T cells. Low IgA, low IgG.
Which is most likely?
a) 22q 11.2 deletion syndrome
b) Bare lymphocyte syndrome type 2
c) X-linked SCID
d) IFN-y receptor deficiency
a) 22q 11.2 deletion syndrome AKA Di George’s
A young adult has a chronic infection with Mycobacterium marinum.
Which is most likely?
a) Bare lymphocyte syndrome type 2
b) X-linked SCID
c) 22q 11.2 deletion syndrome
d) IFN-y receptor deficiency
d) IFN-y receptor deficiency - the others would typically present a lot earlier
A 6 month baby with 2 recent serious bacterial infections. T cells are present - but only the CD8+ subset. B cells are present. IgM present but IgG is low.
What is most likely?
Bare lymphocyte syndrome type 2
A 1 year old boy has recurrent bacterial infections. CD4 and CD8 T cells are present. B cells are absent. IgG, IgA and IgM are all absent.
Which is most likely?
a) Bruton’s x-linked hypoglobulinaemia
b) Common variable immunodeficiency
c) IgA deficiency
d) X-linked Hyper IgM syndrome due to CD40L mutation
a) Bruton’s x-linked hypoglobulinaemia
Recurrent bacterial infections in a child. Episode of pneumocystic pneumonia, high IgM, absent IgA and IgG.
What is most likely?
X-linked Hyper IgM syndrome due to CD40L mutation
Adult with bronchiectasis, recurrent sinusitis and development of atypical SLE.
What is most likely?
Common variable immune deficiency (airway disease common, alongisde recurrent bacterial sinusitis and development of autoimmune disease)
Define immunopathology
Damage to the host caused by the immune response
What is auto-inflammatory disease?
Immunopathology in the absence of an infection. This is caused by an innate immune response. Can be monogenic (rarer) or polygenic (more common).
What is auto-immune disease?
Immunopathology in the absence of infection. Caused by an adaptive immune response. Can be monogenic (rarer) or polygenic (more common).
What are the different factors affecting protein/gene expression?
Mutations - germline or somatic
Epigenetics
MiRNA
What are some examples of monogenic autoinflammatory diseases?
Muckle Wells Syndrome (MWS)
Familial Mediterranean Fever (FMF)
TNF Receptor Associated Periodic Syndrome (TRAPS)
Hyper IgD + Periodic Fever Syndrome (HIDS)
What are some examples of monogenic auto-immune diseases?
Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked syndrome (IPEX)
Auto-immune lymphoproliferative syndrome (ALPS)
What are some examples of poygenic auto-inflammatory diseases?
Crohn’s disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
Which of the following is an example of a monogenic auto-inflammatory disease?
a) Familial Mediterranean Fever
b) Graves’ disease
c) Crohn’s disease
d) Axial spondyloarthritis
e) IPEX syndrome
a) Familial Mediterranean Fever
Which of the following is an example of a monogenic auto-immune disease?
a) Familial Mediterranean Fever
b) Graves’ disease
c) Crohn’s disease
d) Axial spondyloarthritis
e) IPEX syndrome
e) IPEX syndrome
Which of the following is an example of a poygenic auto-inflammatory disease?
a) Familial Mediterranean Fever
b) Graves’ disease
c) Crohn’s disease
d) Axial spondyloarthritis
e) IPEX syndrome
c) Crohn’s disease
What are some examples of polygenic auto-immune diseases?
Rheumatoid arthritis
Myaesthenia Gravis
Pernicious anaemia
Addison’s disease
Systemic lupus erythematosus
Primary biliary cholangitis
What is the gel and coombs classification?
Classification of sin test hypersensitivity reactions according to type of immune response observed:
1) Anapylactic hypersensitivity
2) Cytotoxic hypersensitivity
3) Immune complex hypersensitivity
4) Delayed type hypersensitivity
What are examples of Type 2 antibody driven auto-immune diseases?
Goodpasture disease
Pemphigus vulgaris
Graves’ disease
Myaesthenia gravis
What is an example of a Type 3 Immune complex driven autoimmune disease?
Systemic Lupus Erythematosus
How can we divide polygenic auto-immune diseases?
By whether they are organ specific diseases (Graves’ disease; Hashimoto’s thyroiditis; T1 diabetes; Pernicious anaemia; Myaesthenia gravis; Goodpasture’s disease) or multisystem diseases (Rheumatoid arthritis, SLE, Sjogren’s syndrome; Systemic sclerosis; Dermato/Polymyositis; ANCA-associated vasculitis)
Which Antibodies should you test for multisystem polygenic autoimmune diseases?
Rheumatoid arthritis - Rheumatoid factor, Anti-CCP Antibody
SLE, Sjogren’s, Systemic sclerosis, Systemic sclerosis, Dermato/polymyositis - Anti-nuclear Antibody
ANCA-associated vasculitis - Anti-neutrophil cytoplasmic Antibody
What antibodies should you test for organ-specific auto-immune diseases?
Graves’ disease - IgG antibodies that stimulate TSH receptor - Anti TSH resceptor Ab
Hashimoto’s thyroiditis - Anti TPO Ab, anti thyroglobulin Ab
Type 1 diabetes - Anti B cell antibodies
Pernicious anaemia - Anti-intrinsic factor antibodies
Myaesthenia gravis - Anti ACh receptor antibodies
Goodpasture disease - Anti glomerular basement membrane antibodies
Which of the following auto-antibodies is characteristically found in Myaesthenia gravis?
a) Anti-GAD
b) Anti-thyroglobulin
c) Anti-basement membrane
d) Anti intrinsic factor
e) Anti-ACh receptor
f) Anti-cyclic citrullinated peptide
g) Anti-TSH receptor
e) Anti-ACh receptor
Which of the following auto-antibodies is characteristically found in Pernicious anaemia?
a) Anti-GAD
b) Anti-thyroglobulin
c) Anti-basement membrane
d) Anti intrinsic factor
e) Anti-ACh receptor
f) Anti-cyclic citrullinated peptide
g) Anti-TSH receptor
d) Anti intrinsic factor
What multi-system auto-immune disease is associated with Anti-Ro and Anti-La antibodies?
Sjogren’s syndrome
What is the commonest treatable cause of recurrent miscarriage?
Anti-phospholipid syndrome
What Antibodies do you get in patients with limited cutaneous systemic sclerosis?
ANA
Anti-centromere
What antibodies do you get in diffuse cutaneous systemic sclerosis?
ANA
Anti topoisomerase (Scl70)
Results show +ve ANA, +ve dsDNA, low complement C3 and C4 with -ve results for Ro, La, Sm, RNP, centromere, SCL70 and Jo-1.
What is the diagnosis?
Systemic Lupus Erythematosus
Results show +ve ANCA, -ve ANA, normal complement and raised CRP and ESR. They have pulmonary and renal signs.
What is the likely diagnosis?
ANCA-associated vasculitis
What are the 2 most common clinical manifestations of anaphylaxis?
a) Urticaria and angioedema
b) Breathlessness and wheeze
a) Urticaria and angioedema
(Skin manifestations occurs in 90% patients)
Adults with recurrent meningococcal disease should be screened for defects in which immune system pathway?
a) Neutrophils
b) T lymphocytes
c) Complement
c) Complement
Anti-double stranded DNA antibodies are typically associated with which disease?
a) Systemic Lupus Erythematosus
b) Immune mediated myositis
c) Primary biliary cholangitis
a) Systemic Lupus Erythematosus
What is the definition of multiple myeloma?
Neoplastic proliferation of plasma cells
Results in the massive expansion of a single plasma cell clone
What cytokine do the drugs etanercept and infliximab target?
Tumour necrosis factor - alpha
What primary antibody syndrome is associated with a mutation in Bruton’s Tyrosine Kinase gene?
X-linked agammaglobulinaemia
What is the colloquial name for Type 1 hypersensitivity to latex where there is cross reactivity with some foods?
‘Latex Fruit Syndrome’
Define Kostmann syndrome
Severe congenital neutropenia as a result of failure of neutrophil maturation (<500/uL indicates severe neutropenia)
What test can be used to confirm the diagnosis of Kostmann syndrome or Chronic granulomatous disease?
Nitro-blue-tetrazolium test
Kostmann syndrome - +ve result - bright blue (presence of normal NADPH)
Chronic granulomatous disease - -ve result
What is protein-losing enteropathy?
Caused by coeliac disease, crohn’s disease, Menetrier’s disease.
Severe loss of proteins via the gastrointestinal tract. Loss of protein leads to fewer immunoglobulins being formed (diminishes the adaptive immune response).
What are the immunological features of Di George syndrome?
Causes an absent or hypoplastic thymus as the 3rd and 4th branchial arches are affected. This leads to defective T cell production and maturation, This reduces the number of circulating CD4+ and CD8+ T cells as well as the IgA and IgG levels (via B cell stimulation).
B cell and IgM levels will be normal.
What does the CD40L on T cells do?
Communicates with B cells via CD40 receptor.
Allows the B cell to class switch from IgM to other Ab.
If there is a defect in CD40L, then the patient will have Hyper IgM syndrome. They will have elevated IgM and low levels of IgA, G, E.
What blood results would you expect in leukocyte adhesion deficiency (LAD)?
Extremely high neutrophil count in blood
Positive NBT test.
What is Acquired Immunodeficiency Syndrome (AIDS) characterised by?
Reduced CD4+ T cell count.
What is Wiskott-Aldrich syndrome?
An x-linked recessive immunodeficiency where the T cell-APC interaction is disrupted. It is caused by a mutation in the WASp gene.
What are the clinical signs and symptoms of Wiskott-Aldrich syndrome?
Signs: Thrombocytopenia, raised IgE, raised IgA, reduced IgM, lymphopenia, Anaemia
Symptoms: Itchy skin - Eczema, Nose bleeds, Easy bruiding, GI bleeding
What mutation causes common variable immunodeficiency?
MHC 3 mutation
Failure in B cell differentiation/function
What are the hallmarks of Common variable immunodeficiency?
Reduction in IgG, IgM may be reduced, IgA or IgE may be reduced
Reduction in B cells (failure of differentiation/function)
Associated with the development of autoimmune conditions
Associated with Non-Hodgkin lymphoma
Associated with persistent pneumonia, sinusitis and gastroenteritis
Associated with Streptococcus pneumoniae and Haemophilus influenzae infection
What protein does calcineurin inhibitor Cyclosporine A inhibit?
It inhibits phosphatase calcineurin.
How does Azathioprine work?
Metabolised into 6-mercaptopurine - a purine analogue - that prevents DNA synthesis and inhibits the proliferation of cells (lymphocytes are most affected). Prevents T cell proliferation.
How does Tacrolimus work?
It is a calcineurin inhibitor which inhibits T cell-proliferation by binding to FKBP-1A - this targets T cell activation.
What does a failure in lymphocyte precursors cause?
Severe combined immunodeficiency
How should patients with a complement deficiency be managed?
Vaccinated with meningococcal, pneumococcal and Haemophilus influenzae vaccines
Prophylactic penicillin against meningitis
Medic Alert (carry)
Functional complement assay screening offered for family
What gene is affected in X-linked agammaglobulinaemia?
Bruton’s tyrosine kinase (BTK) gene
How does selective IgA deficiency present?
Mild respiratory and gastrointestinal infections - may recur
2/3 of individuals are asymptomatic
How do primary T-lymphcyte deficiencies present?
Recurrent viral, protozoal and fungal infections
What is the most common form of severe combined immunodeficiency?
X-linked SCID ( mutation in IL2 receptor Gamma gene)
T cell and NK cell negative, B cell positive SCID
What are the signs of adenosine deaminase SCID?
T cell negative, NK cell negative, B cell negative
What are the tx options for SCID?
Bone marrow transplantation
Gene therapy for adenosine deaminase SCID
A 50 year old woman presents to her GP for an NHS check. She has HIV and is compliant with her medications. She has recently moved to the UK and did not receive all her vaccinations as a child. She has never had chickenpox. She mentions that she is going on holiday to Gambia in 2 weeks time. Which of the following vaccinations should she not receive?
a) Hepatitis A
b) Varicella
c) MMR
d) Yellow fever
e) BCG
d) Yellow fever and e) BCG
Which of the following is an indication for IVIG?
a) VZV exposure in pregnancy
b) Rabies exposure
c) Leukocyte adhesion deficiency
d) Chronic lymphocytic leukaemia
e) Hepatitis B exposure
d) Chronic lymphocytic leukaemia
(Would use a specific form of IgG in VZV exposure, Ravies exposure and Hepatitis B exposure)
What is an example of a CTLA4 inhibitor for cancer treatment?
Ipilimumab
Action: mAb binds to CTLA4 on T cells, blocking the immune checkpoint (CTLA-4 on the T cell interacts with CD80 on APC which inhibits T cell activation)
This therefore allows T cell activation and killing of the cancer
Used for: Melanoma
Complications: autoimmunity
What are 2 examples of PD1 inhibitors?
Pembrolizumab
Nivolimumab
Action: mAb binds to PD1, blocking the immune checkpoint (inhibitory interaction between PD1 on T cells and PDL1 on APC) which allows T cell activation and killing of the cancer cells
Indications: Advanced melanoma, metastatic renal cell carcinoma
Complications: Autoimmunity
Which of the following is not a therapeutic option for metastatic melanoma?
a) dendritic cell vaccine
b) CAR T cell therapy
c) ipilimumab
d) tumour infiltrating T cell therapy
e) pembrolizumab
b) CAR T cell therapy - used for B cells - Non-Hodgkin’s lymphoma and ALL
A 65 year old man presents with left flank pain, frank haematuria and weight loss. A CXR reveals lung metastases. Which of the following may be used in his tx?
a) IFN-beta
b) IL-6
c) IL-2
d) IFN- alpha
e) IFN-gamma
c) IL-2
Renal cell carcinoma
Under what conditions of secondary antibody deficiency syndrome would you give IgG replacement therapy?
Underlying cause cannot be reversed
Hypogammaglobinaemia due to drugs, after stem cell transplant, B cell lymphoproliferative disorders
Recurrent/severe bacterial infection despite continuous Abx
IgG < 4.0g/L
Failure of response to vaccine challenge
How is HIV detected and bound to by CD4+ T cells?
The receptor for HIV is the CD4 molecule. This binds to it’s co-receptor on HIV - CCR5 or CXCR4. Gp120 and Gp41 are viral antigens that bind to CD4.
Define isograft
A transplant from an identical twin
Define autograft
A transplant from your self
Define allograft
A transplant from the same species
Define xenograft
A transplant from a different species
Contrast the histology of a T cell mediated rejection and an antibody mediated rejection
T cell mediated rejection: Interstitial inflammation and cell infiltrate
Antibody mediated rejection: Intravascular disease
What promotes immune tolerance?
Oral exposure to allergens
Lots of T regulatory cells wihtin the gut dampen down the immune response and inhibit IgE synthesis
What promotes IgE sensitisation?
Skin and respiratory exposure to allergen
i.e. in disrupted skin barriers like eczema
What are the principles of immune memory?
- Pre-formed pool of high affinity specific antibodies
- Residual pool of specific T and B cells with enhances capacity to respond if re-infection occurs
