Intro to clinical immunology Flashcards
What is the difference between primary and secondary immunodeficiency?
- Primary = defect in immune system
- Secondary = caused by non-immune
What are primary immunodeficiencies?
- Usually genetic
- infrequent but can be life-threatening
- Can be in adaptive or innate immune system
- Frequency - 50% Ab, 30% T-cell, 18% phagocytes, 2% complement
What are the major B lymphocyte disorders?
- X-linked agammaglobulinaemia (Bruton’s)
- Common variable immunodeficiency (CVID)
- Selective IgA deficiency
- IgG2 subclass deficiency
What is X-liked Agammaglobulinaemia?
- First described immunodeficiency
- Bruton’s disease
- Defect in BTK gene on X chr
- Encodes for Bruton’s tyrosine kinase
- Causes a block in B-cell development (stops at pre B-cells) as needed for pre-B cell receptor signalling
- causes recurrent severe bacterial infections
What would investigations for X-linked Agammaglobulinaemia show?
- All Igs absent/ very low
- B cells absent/ low
How do we treat XLA?
- IV Ig - 200-600mg/kg/month at 2-3 week intervals
- Or subcutantaneous Ig weekly
- Prompt antibiotic therapy (URI/LRI)
What is common variable immunodeficiency?
- Commonest symptomatic Ab deficiency
- Presents at any age, but peaks early childhood/ early adulthood
- Recurrent bacterial infections (chest, sinus)
- Autoimmune problems
- Usually missed (exclusion diagnosis -> late diagnosis -> complications)
What would investigations for CVI show?
- B cells normal or low - cant differentiate into plasma cells
- One or more Igs low
- T cells normal, CD4 T cells can be low
How do we treat CVI?
- IV Ig
- Antibiotic prophylaxis
What other antibody deficiencies are there?
Selective IgA
- 1:400-800
- most cases asymptomatic, some have resp, urogenital or GI tract infections
- Low serum and secretory IgA
Specific Ab deficiency with normal Igs
- Hep B vaccination - 5% dont respond
- Recurrent bacterial infections (URI/LRI)
What is severe combined immunodeficiency (SCID)?
- Involves both B and T cells
- 50-60% X-linked, rest AR
- Well at birth, probs after 1st month
- Diarrhoea, weight loss, persistent cadidiasis
- Severe bacterial/ viral infections
- Failure to clear vaccines
- Usual infections - pneumocystis, CMV
What causes SCID?
- RAG-1/ RAG-2 defect -> no T and B cells
- Common cytokine receptor gamma-chain defect (signal transduction component of ILs); IL-7 needed for survival of T-cell precursors -> defective T cell development -> lack in B cell help (low Ab)
- Adenosine deaminase deficiency (ADA) - causes accumulation of deoxyadenosine and deoxy-ATP - toxic for rapidly dividing thymocytes
- Bare lymphocyte syndrome (MHCI or II)
What would investigations for SCID show?
- Low total lymphocyte count
- Very low/ absent T, normal/ absent B (if gamma-chain defect affecting IL-15, then absent NK)
- Igs low
- T cell function decline (proliferation and cytokines)
How do we treat SCID?
- Isolation
- Dont give live vaccines
- Blood products from CMV negative donors
- IV Ig
- Treat infections
- BM/HSC transplant
- Gene therapy
What is the prognosis for SCID?
- Dependent on promptness of diagnosis, donor match and infections pre-transplant
- can be as high as 80%
What is DiGeorge syndrome?
- 22q11 deletion - failure of development of 3rd and 4th pharyngeal pouches
- Complex array of developmental defects
- Dysmorphic face: cleft palate, low-set ears, fish shaped mouth
- hypocalaemia, cardiac abnormalities
- variable immunodeficiency (absent/ reduced thymus -> affects T cell development)
What is bare lymphocyte syndrome?
- Mutations in TF that regualte expression of MHC class II gene
- no MHC II, no CD4 T-cell development
- Defect in CD4+ T cells, defective help for B cells, Ab production defects = combine T and B cell immunodeficiecny
What is Wiskott-Aldrich syndrome?
- X-linked
- Defect in WASP (protein involved in actin polymerisation -> defect in signalling)
- Thrombocytopaenia, eczema and infections
- Progressive immunodeficiency
- Progressive decrease in T cells and their proliferation
- Ab production (decreased IgM and IgG, High IgE and IgA)
What is ataxia-telangiectasia?
- AR
- Defect in cell cycle checkpoint gene - ATM senses DNA damage -> activates p53 -> apoptosis of cells
- ATM stabilises dsDNA break complexes during VDJ recombination - defect = prob generating lymphocyte Ag receptors and development
How does AT present?
- Progressive cerebellar ataxia (poor coordination)
- Telangiectasia - small dilated vessels (ear lobes and conjungtivae)
- immunodefiency (B and T)
- ## URI/LRI
What is hyper-IgM syndrome?
- Mutations in gene for CD40L, or loss of function mutations in CD40 or AID genes
- Serum - increased IgM, very low IgG, no A or E
- Normal numbers of B and T cells
- Recurrent infections (low opsinisation)
How does Hyper-IgM cause its problems?
- Defect in T cell help to B cells/ macrophages
- CD40L mutation - no binding to B cells, no B cell activation. Also no Macrophage binding or activation
Problem with AID -> problem with Ig class/ isotype switching and affinity maturation
What phagocyte defects are there?
- Quantitative (decreased number)
- Qualitative - Chronic granulomatous disease, Chediak-Higashi, Leukocyte adhesion defects (LADs)
What is chronic granulomatous disease?
- Defective oxidative killing of phagocytosed microbes
- Mutation in NADPH oxidase
- XLR
- Susceptibility to infection with catalase +ve bacteria
How do we diagnose CGD?
- NBT test (nitroblue tetrazolium reduction) - stain
- Flow cytometry assay dihydrorhodamine
What is Chediak-Hidashi syndrome?
- rare genetic disease
- Defect in LYST gene gives defective lysosome trafficking - failure of phagolysosome fusion
- Repetitive severe infections
How do we diagnose C-H syndrome?
- decreased number of neutrophils
- Neutrophils have giant granules
What is leukocyte adhesion deficiency (LAD)?
- Defect in integrins
- AR
- Decreased chemotaxis of neutrophils to damaged area, and less integrins on phagocytes
- Recurrent skin infections, intestinal and perianal ulcers
What defects are there in TLR signalling?
- Rare
- Defect in TLR3 -> recurrent encephalitis (HSV)
- Defect in MyD88 (signalling component downstream many TLRs) -> bacterial pneumonia
What complement deficiencies are there?
- Recurrent infections (neisseiria - MAC deficiency)
- Severe/fatal pyogenic infections (C3 deficiency)
- SLE-like syndrome (C1q, C2, C4 deficiency)
- Hereditary angiogenic oedema - failure to inactivate complement (C1 inhibitor deficiency)
What are the aims of PID treatment?
- Minimise/ control infection
- Replace defective/ absent component
- Prompt treatment of infection
- Prevent infection - isolation, prophylaxis, vaccination (NOT LIVE)
- Nutrition
What may cause SID?
- Infections
- Malignancy
- Extremes of age
- Nutrition
- Chronic renal disease
- Splenectomy
What infections may cause SID?
- Viral - HIV, CMV, EBV, measles, flu
- Chronic bacterial - TB, leprosy
- Chronic parasitic - malaria
- Acute bacterial - septicaemia
What malignancies may cause SID?
- myeloma
- lymphomas
- leukaemias
How can extremes of age cause SID?
- Premature - infants less than 6 months use maternal IgG. Premature delivery interrupts placental transfer of IgG
- Old age - decline in normal function
What nutritional may cause SID?
Starvation, anorexia, iron deficiency protein-losing enteropathies
How can chronic renal disease cause SID?
Uraemia
Dialysis
Nephrotic syndrome
What other problems can cause SID?
- Burns
- Toxins - smoking, alcohol
- Immunosuppressive drugs
- Transplant
- trauma and surgery
Why do we do BMT?
- Reconstitution of full haematopoeiti system by transfer of pluripotent stem cells
- Used to replace defective, absent or malignant cells
What are the different types of BMT?
By donor source
- Allogenic - genetically matched
- Autologous - pt is the source
By site of harvest
- Puncture and aspiration of BM
- Peripheral stem cells from blood
- Umbilical
What are some complications of BMT?
- Infection (CMV, EBV, adenovirus)
- Graft failure
- Graft vs host disease
What causes GvHD?
- transplanted immunocompetent T cells of donor respond against recipient
- Acute (rare now die to improved matching)
- Chronic (main cause of death in BMT)
- Graft vs tumour (leukaemia)
