Immunology Flashcards
Most common type of SCID?
X-SCID (45%)
yC (common gamma chain) defect
T-, NK-
B+ (high B cell counts) but dysfunctional as abnormal cell surface receptors
JAK-3 SCID
Normal function of yC
Similar profile to X-SCID
AR, <10% of cases
T-, B+, NK-
IL7Ra deficiency
Growth factor receptor
T-, B+, NK+
3rd most common type of SCID (11%), AR
ADA deficiency
2nd most common SCID (15%)
AR
Involved in metabolic function of T cells
T-, B-, NK-
Other effects (neuro, cognitive, hearing, visual, movement disorders, hypotonia)
Not fully curative with HSCT
CD3 chain deficiencies
Components of the TCR complex (type of SCID)
T-, B+, NK+
CD45 deficiency
Type of SCID (rare)
aka lymphocyte common antigen/protein tyrosine phosphatase
T cell receptor signalling and T cell development in the thymus
T-, B+, NK+
RAG1/RAG2/artemis deficiency/cerunnos deficiency/DNA ligase 4 deficiency
Type of SCID
RAG1/RAG2 mutations can also cause Omenn syndrome
T-, B-, NK+
AR inheritance
Result of deficiency of CD40 on T cell?
Hyper IgM: cells unable to perform class switching therefore have normal/high IgM but all other Ig deficient
Normal B cell and T cell numbers
Clinical features of Hyper IgM?
Cryptosporidial/giardia diarrhoea
Recurrent bacterial infections
Sclerosing cholangitis
Int neutropenia
Reduced vaccine responses
Defect in RAG1/RAG2 somatic recombination of VDJ?
Omenn syndrome
- AR form of SCID
- low B and T cells
- similar to GvHD
Clinical features of Omenn syndrome
Opportunistic infections
Similar to GvHD (limited recombination of T cells -> abnormal population of self reactive T cells)
- neonatal erythroderma, eosinophilia, FTT, lymphadenopathy, splenomegaly, diarrhoea
Recurrent infections, thrombocytopenia, eczema?
Wiskott Aldrich syndrome
X linked recessive, WAS mutations (Xp11.23)
WASp = cytoskeletal actin element in haematopoietic cells
Can have autoimmune manifestations (ITP, vasculitis)
Investigation findings in WAS?
Thrombocytopenia with SMALL platelets
Low IgM, high IgA/E, variable IgG
Eosinophilia
Specific gene testing
Lymphocyte count and subsets can be variable (not diagnostic)
Cause of ataxia telangiectasia?
AR defect in ATM gene on Ch11 - enzyme involved in cellular response to DNA damage, repair
Clinical features of ataxia telangiectasia?
Ataxia, decline in motor function, oro-motor incoordination
Telangiectasia (eyes, sun exposed areas)
Immune deficiency: sinopulmonary, warts, molluscum, lesser risk of opportunistic infections
Malignancy risk
Investigation findings in ataxia telangiectasia?
Low/absent IgA
Varying degrees of IgM and IgG deficiency
Reduced T and B cell counts
Immunological consequence of DiGeorge?
Thymic aplasia - some have poor T cell production, 1-2% have absent/severely low T cells
The majority have less severe/mild deficiency and do not need therapy
Non invasive recurrent candida infections of skin, nails and mucosa?
Chronic mucocutaneous candidiasis
Aetiology of chronic mucocutaneous candidiasis?
Primarily Th17 pathway defects
CARD9
STAT3 (AD Hyper IgE)
DOCK8 (AR Hyper IgE)
IL-17Ra
AIRE gene = APECED (autoimmune polyendocrinopathy - adrenal, thyroid, hypoparathyroid, DM, candidiasis, ectodermal dysplasia)
AR variable immunodeficiency to viral infections, dwarfism, brittle hair?
Cartilage hair hypooplasia
Fatal EBV infections, lymphoma and combined immunodeficiency?
X linked lymphoproliferative syndrome
XLP1 = SH2DIA: positive signalling for CD8 and NK cell proliferation
XLP2 = XIAP: regulator of lymphocytic apoptosis; colitis, IBD
X linked disorder, IUGR, microcephaly, pancytopenia, NK cell dysfunction, progressive combined immunodeficiency
Dyskeratosis congenita (Hoyeraal-Hriedarsson)
AR, absent T cells, short stature, IUGR, renal failure, bone marrow failure, stroke, enteropathy
Schimke immune-osseous dysplasia
AR, normal T cells, reduced B cells with elevated IgE and IgA, respiratory and skin infections, ichythosis, bamboo hair (trichorrhexis nodosa), growth failure, risk of atopy
Netherton syndrome
Inhibitory TCR that competes for co-stimulation
CTLA4 deficiency:
Lack of CTLA4 -> unregulated T cell activation and autoinflammation
Clinical features of CTLA4 deficiency
Low Ig GAM (CVID like phenotype)
Multi organ autoimmunity: cytopenia, IBD, psoriasis, thyroid, bronchiectasis, generalised lymphadenopathy
Mutations in FOXP3 gene?
IPEX
Early onset insulin dependent DM, severe watery diarrhoea, FTT, dermatitis
Haemolytic anaemia, thrombocytopenia
IPEX
Clinical features of IPEX?
Early onset insulin dependent DM, severe watery diarrhoea, FTT, dermatitis
Haemolytic anaemia, thrombocytopenia
Cause of activated P13KCD syndrome?
Downstream signalling in immune regulation
AD GOF mutations -> hyperactivation of signalling pathways
Clinical features of activated P13KCD syndrome?
Immune deficiency (herpes, EBV, CMV)
Autoimmunity
Lymphoproliferation, lymphoma
Neurodevelopmental delay and growth deficits
Cause of X linked agammaglobulinaeia
Bruton’s tyrosine kinase (Btk) deficiency: pre B cell arrest, essential element of BCR signalling pathway
Most common cause of agammaglobulinaemia
Infant males with recurrent bacterial infections, severe enteroviral infections, absent lymphoid tissue?
X linked agammaglobulinaemia
Features of X linked agammaglobulinaemia?
Infant males (6-18 months) with recurrent bacterial infections, severe enteroviral infections, absent lymphoid tissue
Investigations in X linked agammaglobulinaemia
Neutropenia (10-25% during sepsis)
Absent B cells
Generally reduced/absent Ig GAM
Absent vaccine responses
Management of agammaglobulinaemia?
3-4 weekly IVIG
Avoid live vaccines
Antibiotic prophylaxis in some cases
Cause of CVID?
Inability of B cells to differentiate into plasma cells capable of secreting all immunoglobulin types
Clinical features of CVID
Upper and lower resp infections and chronic GI infections
Prolonged giardia
Pulmonary manifestations in 85% (bronchiectasis)
Lymphoproliferative and granulomatous manifestations
Granulomatous interstitial lung disease
Lymphadenopathy, splenomegaly
Testing antibody responses in CVID?
T dependent isotope switched plasma cell response (tetanus, diphtheria, prevenar, MMR)
T independent (polysaccharide in conjugate vaccine) IgM pneumovax 23
Overview of IgA deficiency
Defect in IgA
Normal IgG, M, D and E
Normal T cell, phagocytic and complement function
1/500 Caucasians
Clinical features of IgA deficiency
Varies from asymptomatic to significant illness
Recurrent ear infections, sinusitis, bronchitis, pneumonia
GI and chronic diarrhoea
25-30% develop autoimmune features
Overview of specific antibody deficiency
Inability to produce IgG to specific type of organisms
Particularly polysaccharide encapsulated organisms
Normal Ig levels otherwise
Impaired polysaccharide vaccine responses but normal responses to protein vaccines
Overview of transient hypogammaglobulinaemia
Persistence of nadir in Ig seen after birth
Half life of IgG = 30 days
No complications, normal growth, sinopulmonary infections (no opportunistic infections)
Low Ig with recurrent infections, thymic tumour, mainly seen in adults, low eosinophil count
Immunodeficiency with thymoma (Goods syndrome)
B12 deficiency anaemia, FTT, leukopenia, hypogammaglobulinaemia
Transcobalamin II deficiency
AR defect in CXCR4, severe warts, low but not absent Ig, neutropenia?
Warts, hypogammaglobulinaemia, infection, myelokathexis (WHIM syndrome)
BM failure to release granulocytes = myelokathexis
Treatment with Ig and G-CSF
Light chain defect, AR inheritance, but highly variable and patients may be asymptomatic
Kappa chain deficiency
Heavy chain deficiency
Extremely rare, single gene defects that encode multiple immunoglobulin
Patients only make one or a few types of Ig
Highly variable phenotype
Overview of chronic granulomatous disease
67% X linked, 33% AR
Disorder of neutrophil function
Gp91phox subunit = CYBB Xp21.1 = X linked CGD is most common (65%)
Clinical features of CGD
IBD
Gingivitis, stomatitis
GU infections, granulomas
Pneumonitis
Chorioretinitis
Adenopathy >90% and hepatosplenomegaly >90%
Types of infection in CGD
Pneumonia 79%
Abscesses (caseating, inflammatory and granulomatous, hard to treat) 68% - mostly subset but can occur in liver or lung
Investigations in CGD
Hypergammaglobulinaemia
NBT - reduction in oxidative burst
Dihydrorhodamine oxidation (DHR) - attempts to stimulate neutrophils with PMA and incubation, see if they can produce peroxide
5 main organisms in CGD
Aspergillus
Staph aureus
Burkholderia cepacia
Serratia
Nocardia
Management of CGD
ABx prophylaxis (bactrim)
Immunomodulatory therapy
yIFN (stimulates release of NO)
Steroids
BMT
Physiology of leukocyte adhesion deficiency
Failure of neutrophil migration
Problems with beta2 integrals (e.g. CD11, CD18 in LAD type 1)
Clinical features in LAD
Delayed separation of the umbilical cord (normally 10-14 days, can be up to 3 weeks)
Severe aggressive infections
Most common type of LAD?
LAD1
Defect in common beta chain of beta2 integral, impaired firm adhesion of leukocytes
Severe phenotype with <1% normal expression of CD18
Clinical features of LAD1
Delayed cord separation, omphalitis without pus
WBC >15 even when well
Destructive gingivitis
Severe necrotising bacterial infections (staph and GNB)
Absent pus!!!
Types of LAD
LAD1 - impaired adhesion
LAD2 - impaired rolling
LAD3 - impaired activation
Kostmann syndrome
AR HAX1 gene defect, severe congenital neutropenia
Treat with G-CSF and BMT
Cyclic neutropenia
AD ELA1 gene defect
Neutropenia lasting 1 week, in cycles of 2-4 weeks (need to check twice per week for multiple weeks)
Benign chronic neutropenia
Non-life threatening, asymptomatic chronic neutropenia
Glycogen storage disease type 1b
Metabolic disorder with accumulation of glycogen in end organs
Defect in glucose-6-phosphate transporter 1
Leads to neutropenia, poor granulocyte function, hepatomegaly, hypoglycaemia
Beta actin deficiency
Similar mechanism to LAD
General chemotaxis: periodontitis and early tooth loss
Chediak Higashi syndrome
AR disorder with microtubule polymerisation defect
Impaired phagolysosome formation (i.e. phagocytosed bacteria are not destroyed by lysosomal enzymes)
Cx: EBV lymphoproliferative disease, HLH
Oculo-cutaneous albinism (partial), sun sensitivity, photophobia, variable infection risk (S. aureus), neuropathy
Chediak Higashi syndrome
Griscelli syndrome
AR disorder due to accumulation of melanosomes in melanocytes: hypomelanosis
Only type 2 (mutation in RAB27A) causes PID
Haemophagocytic syndrome common
Early BMT recommended
Partial albinism, frequent pyogenic infections, acute episodes of fever, neutropenia and thrombocytopenia
Griscelli syndrome
Classical complement pathway deficiency
C1q/r/s, C2 and C4 deficiency most common
Strong association with autoimmune disease
Partial C4 def in 30% of population
Infections with encapsulated bacteria common
Alternative pathway deficiency
Recurrent Neisseria
Actions of C3
Opsonisation
Solubilisation of immune complexes
Enhance bacterial killing via MAC
Potentiating humeral response
C3 deficiency
Half life 60 microsec
Deficiency can be primary or secondary with excessive activation and consumption but even small amounts are protective against infections
Severe recurrent pyogenic infections
MyD88 and IRAK4 deficiency
Susceptible to invasive (deep seated) pneumococcal, S. aureus, P. aeruginosa but normal resistance to other bacteria
Skin, bone, brain, organ abscesses
Onset within 2 years of life
NEMO deficiency
Ectodermal dysplasia (thickened skin, conical teeth, absent sweat glands, thin hair, incontinentia pigmenti)
Infections - invasive pyogenic (pneumococcus, staph), mycobacterial
X-recessive, Nf-k B essential modulator/IKK gamma regulates gene expression
Ix: absence of pneumococcal vaccine response despite relatively normal Ig levels
