Immunology Flashcards
monogenic auto-inflammatory diseases?
and autoimmune diseases?
Mechanisms?
autoinflammatory
1. Familial mediterranean fever(IL 1). Treat with colchicine. Long term risk of AA amyloidosis -> deposits in Kidney -> nephrotic syndrome
2. TRAPs
autoimmune -
1. ALPS = autoimmune lymphoproliferative syndrome. FAS mutation!! Lymphocytes don’t undergo apoptosis = high lymphocyte numbers!! LYMPHOMA, CYTOPENIA
2. IPEX = mutation in foxP3. 3DS diabetes, dermatitis and diarrhoea. symptoms. Failure of treg cells to bring about peripheral tolerance.
3. Autoimmune polyendocrine syndrome type 1. APSI. Mutation in AIRE!! Failure of central tolerance. Many autoimmune conditions. Also known as APACED.
Without Aire your body will CHAR = chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency, recurrent Candida infections) hypothyroidism
Familial mediterreanean fever
pathology?
presentation
complications
investigation
management
Autosomal recessive condition
Mutation in MEFV gene
MEFV gene encodes pyrin-marenostrin
Pyrin-marenostrin expressed mainly in neutrophils
Failure to regulate cryopyrin driven activation of neutrophils
Periodic fevers lasting 48-96 hours associated with:
Abdominal pain due to peritonitis
Chest pain due to pleurisy and pericarditis
Arthritis
Rash
AA amyloidosis -> nephrotic syndrome
high CRP, high serum AA
genetic test
colchicine
Immune dysregulation, polyendocrinopathy, enteropathy, X- linked syndromeIPEX pathology? presentation?
Mutations in Foxp3 (Forkhead box p3) which is required for development of CD25+Treg cells
Failure to negatively regulate T cell responses
Autoreactive B cells
limited repertoire of autoreactive B cells
Autoimmune diseases
Diabetes Mellitus
Hypothyroidism
Enteropathy
Eczem
‘Diarrhoea, diabetes and dermatitis’
genetic test
Auto-immune lymphoproliferative syndromeALPS pathology? presentation?
Mutations within FAS pathway
Eg mutations in TNFRSF6 which encodes FAS
Disease is heterogeneous depending on the mutation
Defect in apoptosis of lymphocytes
Failure of tolerance
Failure of lymphocyte ‘homeostasis’
High lymphocyte numbers with large spleen and lymph nodes
Auto-immune disease
commonly auto-immune cytopenias
Lymphoma
genetic test - look for mutations in FAS pathway
polygenic auto-inflammatory disease examples
mutations identified in chrons?
chrons - IBD1, NOD2
ulcerative colitis
osteoarthritis
giant cell arthritis
Takayasus arteritis
Polygenic autoimmune disease examples
Rheumatoid arthritis Systemic lupus erythematosus
Myaesthenia Gravis Primary biliary cholangitis
Pernicious anaemia
Addison disease
examples of mixed pattern diseases
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome
Axial spondyloarthritis
presentation?
gene associations?
treatment?
pain in sacroiliac joints, in entheses
Low back pain and stiffness
Enthesitis
Large joint arthritis
associated with HLAB27 mostly
but also IL23R, IL32
Treatment
Non-steroidal anti-inflammatory drugs
Immunosuppression
Anti-TNF alpha
Anti-IL17
Hypersensitivity types/groups
Type I: Anaphylactic hypersensitivity
- Immediate hypersensitivity which is IgE mediated – rarely self antigen
Type II: Cytotoxic hypersensitivity
- Antibody reacts with cellular antigen
Type III: Immune complex hypersensitivity
- Antibody reacts with soluble antigen to form an immune complex
Type IV: Delayed type hypersensitivity
- T-cell mediated response
conditions with Type 2 hypersensitivity
goodpastures disease
pemphigus vulgaris
graves disease
myasthenia gravis
conditions with type 3 hypersensitivity
SLE
conditions with type 4 hypersensitivity
insulin dependent diabetes mellitus
antibodies seen in hashimotos thyroiditis?
anti thyroid peroxidase
anti thyroglobulin
Investigation of Connective Tissue DiseaseSLE, Sjogrens, Systemic sclerosis, Idiopathic inflammatory myopathy
they are all ANA+ve
ENA+ve:
1. Ro, La, Sm, RNP - SLE, sjogrens
2. SCL70 - diffuse cutaneous systemic sclerosis
3. Centromere - crest
cytoplasmic:
t-RNA synthetase (Jo1) - myositis
dsDNA+ve:
SLE
state the 3 small vessel vasculitis that are associated with ANCA
1. microscopic polyangitis - P-ANCA
2. granulomatosis with polyangitis - C-ANCA
3. eosinophilic granulomatosis with polyangitis - P-ANCA
p-anca vs c-anca
p anca = antimyloperoxidase
c anca = antiproteinase 3
TH2 immune response
IL4, IL5, IL13
mast cells cross link IgE -> release of histamines and leukotrienes -> worm and allergen expulsion
increased secretion of pro-inflammatory innate cytokines by PBMC following exposure to environmental microbial product may protect against development of asthma
most appropriate initial test for food allergy with urticaria and angioedema?
skin prick test
anaphylaxis treatment
adrenaline
60 year old with hypotension and rash during surgery, what test will you use to diagnose anaphylaxis?
serial mast cell tryptase -> quick turnaround
two types of immune response to infection
cell death or extensive damage -> microbial PAMP and host DAMP -> type 1 and 3 immune responses
cell stress or tissue pertubation -> host DAMP >>> microbial PAMP -> type 2 immune response
type 1 immune response is directed against? how does it work?
Intracellular pathogens!!!
CD4 TH1 cell activation -> secretion of interferon gamma which activates macrophages and CD8 T cells and CD4 also interacts with b cell using IL21 and interferon gamma to secrete antibodies, IgG>IgA
type 3 immune response is directed against? how does it work?
Extracellular bacteria and fungi!!!!!!
CD4 TH17 -> IL17 -> neutrophil
CD4 -> IL22 -> maintain epithelial cell integrity
igA>IgG
type 2 immune response is directed against? how does it work?
Extracellular parasites!!!!!
CD4 TH2 -> IL 4, 5 AND 13 -> mast cells, basophils, eosinophils
b cell -> IgE
Features of marginal zone b cells?
T cell independent
protect against encapsulated organisms
found in spleen
features of extrafollicular b cells
rapid response
respond to protein
t cell dependent and independent
memory
short lived plasma cells
features of germinal centre b cells
t cell dependent
respond to protein
memory
long lived plasma cells
structure of immuniglobulins and function of each part.
2 fab units
1 fc unit -> isotype class switching, ig subclasses, modification of hinge region, glycosylation
Fcr binding causes complement release, phagocytosis etc
what is the most common cause of inborn errors of immunity?
antibody deficiency syndromes
thus, b cells must important cellular component
causes of genetic succeptibility to Tuberculosis
1. one cause is Variant in TYK2 -> signalling protein involved in Type 1 immune response
impairs IL23
80% chance of TB disease if homozygous
2. mutation in IL12
causes of genetic succeptibility to covid19?
defects in type 1 interferon
some patients have antibodies that inhibit type 1 interferon
what conditions are associated with inborn errors of immunity?
inborn errors of metabolism and autoimmune dieases are often linked, especially autoimmune diseases seen in children -> cytopenias
autoinflammatory diseases eg familial mediterranean fever
allergic disease eg eczema, eosinophilia and IgE may be a sign of inborn errors of immunity, eg sever atopy + susceptibility to infection
early onset viral cancers may be a sign of inborn errors of immunity eg EBV succeptibility in combined immune deficiency syndromes
in history ask about immune deficiency and consanguity
most common inborn error of immunity?
selective IgA deficiency
first line blood tests for inborn errors of immunity?
FISH
Full blood count -> look at neutrophil and lymphocyte count
Serum Immunoglobulins
Serum complement
Hiv test
others:
measure concentration of vaccine antibodies - failure to respond to vaccination is a sign
name inborn errors involving the innate immune system
neutrophil:
1. neutropenia syndromes:
- chronic benign neutropenia (asymptomatic, no treatment needed)
- severe congenital neutropenias
2. defects in neutrophil function:
- leukocyte adhesion deficiency syndrome (defect in binding to endothelium)
- Chronic granulomatous disease (defect in generation of reactive oxygen speicies)
complement:
1. C1-C4-2
- SLE in C1Q deficiency 90% of time
- succeptibility to encapsulated bacteria infections -> hib, strep pneumoniae
2. Alternative pathway
- neisseria meningitis (properidin)
3. C3
- C3 glomerulopathy
4, Terminal complement pathway deficiency
- neisseria meningitis
- disseminated gonoccocal infection
5. MBL deficiency
up to 30%. of population, not significant
6. C1 INHIBITOR deficiency
- recurrent episodes of angioedema of skin, abdomen, larynx
- Low C4, normal C3
- treat with C1 inhibitor NOT adrenaline
vaccination and prohylactic antibiotics to people with complement deficiencies
Leukocyte adhesion deficiency
pathology?
clinical features?
management?
deficient CD18 expression on neutrophils, so not enough to bind to ICAM1. neutrophils cant exit blood stream to tissues
- delayed separation of umbilical cord
- very high neutrophil counts
- absence of pus formation
stem cell transplant
Chronic granulomatous disease
pathology?
clinical features?
management?
NADPH oxidase deficiency. oxygen free radicals cant be generated which combine with MPO to form HCl/bleach which kills pathogens
bacterial, fungal infections, increased risk of TB. skin lymph nodes, liver, bone, chest. gastrointestinal and genitourinary inflammatory disease
cotrimoxazole and itroconazole prophylaxis
ifn gamma, stem cell and gene therapy
name inborn errors involving lymphoid precursors
T and B cell progenitors:
1. SCID
T cell progenitors:
1. Di George
SCID
pathology?
clinical features?
management?
which organism is NOT associated with SCID?
Defects in generation of lymphoid precursors in bone marrow. absent or dysfunctional t cells, affecting humoral response
multiple recurrent infections and opportunistic infections
usually unwell by 3 months of age
low lymphocyte count = diagnostic
low cd3
low serum immuniglobulins
stem cell transplantation
influenza A not associated
22q11.2 deletion syndrome
pathology?
clinical features?
management?
defect in t cell maturation/selection in thymus
most common chromosomal deletion syndrome
failure of pharyngeal arch to develop;
- craniofacial structures
- thymus
- parathyroid glands, aortic arch
- cardiac outflow tract
classic triad of immune deficiency, hypoparathyroidism, congenital heart disease. but can present differently
5% reduced tcell numbers which resolve
state antibody deficiency syndromes
selective IgA deficiency
CVID
XLA
Selective IgA deficiency
pathology?
clinical features?
management?
most common
- allergic diseases
- Sinopulmonary and enteric diseases
- Gi cancers
- autoimmune disease
CVID
pathology?
clinical features?
diagnosis?
management
adult onset -> median age 35
most common antibody deficiency in adults
- recurrent sinopulmonary infection with encapsulated bacteria. otitis media and hib conjuctivitis
- repeated chest and sinus infections -> bronchiectasis, recurrent sinusitis
- enteric, skin infections
- autoimmune disease
- granulomatous disease!!! - not just chronic granulomatous disease
- lymphoproliferative disease
diagnosis?
1. over 4 years
2. reduction in IgG and IgA or M
3. poor vaccine response
4. exclude other causes of antibody deficiency - b cell cancers, drugs
lung disease treatment
IgG replacement
XLApathology?
clinical features?
management?
mutation in BTK - Bruton Tyrosine Kinase
succeptibility to disseminated enteroviral infection if not on IgG replacement
neutropenia can be a feature
chronic/acute lung disease = most common cause of death
describe 4 ways to boost the immune response
1. vaccination
2. replacement of missing components - BMT, antibody/immunoglobulin replacement for primary antibody deficiencies or secondary eg in hematological malignancies or after BMT
3. blocking immune checkpoints
4. cytokine therapy - eg interferon alpha in hepatitis, interleukin 2 in renal cell cancer, interferon gamma in chronic granulomatous disease
name some live attenuated vaccines
*learn as you cant give to immunosuppressed
MMR - VBOY
MMR
Varicella
BCG!!!
Oral polio (Sabin), Oral typhoid
Yellow fever
Influenza (Fluenz tetra for children 2-17 years)
name some inactivated vaccines
Influenza (inactivated quadrivalent), Cholera, Bubonic plague, Polio (Salk- injected)!!!, Hepatitis A, Pertussis, Rabies
name some component/subunit vaccines
Hepatitis B (HbS antigen), HPV (capsid), Influenza (recombinant quadrivalent - less commonly used)
name a condition that immunoglobulin replacement therapy can be used in
x linked hyper IgM
Nivolumab and Pembroluzimab
mechanism?
indication?
antibodies that bind to PD1. blocks immune checkpoint, cause T cell activation
indicated in:
advanced melanoma
metastatic renal cell cancer
ipilimumab mechanism?
indication?
antibody binding to CTLA4 blocks immune checkpoint, cause T cell activation
indicated in advanced melanoma
Describe ways of suppressing immune response
1. Steroids
2. Anti-proliferative agents (inhibit DNA synthesis)- eg cyclophosphamide, mycophenolate, azathioprine
3. Plasmapheresis - removal of pathogenic antibodies
4. Inhibitors of cell signalling - MTOR, JAK, PDE, and Calcineurin inhibitors
5. Agents directed at cell surface antigens - eg rituximab/anti-cd20
6. Agents directed at cytokines and their receptors - eg anti tnf alpha
side effects of anti proliferative agents?
Bone marrow suppression
Infection
Malignancy
Teratogenic
Cyclophosphamide key side effects?
Bone marrow suppression
Hair loss
Sterility (male>>female)
Haemorrhagic cystitis
Malignancy - Bladder, Haematological, Non-melanoma skin cancer
Infection - Pneumocystis jiroveci
Azathioprine key side effects?
bone marrow suppression
hepatotoxicity
infection
Mcophenalate motil key side effects?
1. Bone marrow suppression Infection
2. Infection:
- Particular risk of herpes virus reactivation
- Progressive multifocal leukoencephalopathy (JC virus)
indications for plasmapheresis?
Severe antibody-mediated disease:
- Goodpasture syndrome - Anti-glomerular basement membrane antibodies
- Severe acute myasthenia gravis- Anti-acetyl choline receptor antibodies
- Antibody mediated transplant rejection/ABO incompatible
name different drugs that inhibit cell signalling
and use
1. Calcineurin inhibitors - ciclosporin, tacrolimus - used in transplantation, sle, psoriatic arthritis
2.MTOR inhibitors - Rapamycin, sirolimus - transplantation
3. PDE 4 inhibitors - ampremilast used in psoriasis and psoriatic arthritis
4. JAK inhibitors
name agents directed at cell surface antigens
directed at T cells:
- Rabbit anti-thymocyte globulin - used in allograft rejection
- Basiliximab – anti-CD25 - allograft rejection, transplants
- Abatacept – CTLA4-Ig - rheumatoid arthritis
directed at B cells:
Rituximab – anti-CD20 - lymphoma, rheumatoid arthritis, SLE
Targeting lymphocyte migration:
- Vedolizumab – anti-a4b7 integrin - used in IBD
name agents targeting cytokines and their receptors?
antibodies in asthma/eczema?
anti-TNF alpha antibodies - infliximab, adalimumab, certolizumab, golimumab
TNF alpha antagonist - etanercept
anti-IL6 antibodies - tocolizumab,!! sarilumab!! - IL6 targeting important for rheumatoid arthritis!!!
antibody against IL23 - guselkumab or antibodies against IL17 secukinumab- psoriasis, psoriatic arthritis
anti-rank ligand antibody eg denosumab - osteoporosis
IL 4, 5, and 13 in asthma - target them
side effects of immunosuprression with drugs?
infection
malignancy
autoimmunity
IL1 drives what conditions?
IL6 drives what conditions?
IL 17/23 pathway drives what conditions?
IL 4/5/13 drive what conditions?
RANK pathway drives what condition?
TNF alpha can be targeted for what diseases?
*not really expected to know drug names for exam
IL1 = gout, familial mediterranean fever, adult onset stills disease
IL6 - rheumatoid arthritis!
IL17/23 pathway - axial spondyloarthritis, psoriasis! , psoriatic arthritis.(essentially drive spondylarthritis group "PAIR") IBD is IL23 only. (note, Not effective for RA)
IL 4/5/13 - asthma, eczema,
RANK L = osteoporosis
TNF Alpha = rheumatoid arthritis,! psoriasis!, psoriatic arthritis, spondyloarthritis, IBD, familial mediterannean fever
antibody mediated transplant rejection options
eculizimab
velclade - proteosome inhibitor
rituximab
intravenous Ig
plasma echange
1,1,0 Mismatch means what?
1A, 1B, 0 DR
which cells mediate damage in effector phase of t cell organ transplant?
T cells and monocytes/macrorophages
what drug is administered after acute t cell mediated organ rejection
methylprednisolone!!!
high dose, 3 days in a row
main cell type injured in effector phase of antibody mediated rejection?
endothelial cells
hla match rate in parent to child
3/6
