Immunology Flashcards
Estimated prevalence of 1ry immunodeficiency (excluding IgA and IgG subclass deficiency)
1 in 100 000
Some Secondary Immunodeficiencies
• Infections (e.g. HIV) • Malignancy (and treatment thereof) • Extremes of age • Severe malnutrition • Drugs (e.g. corticosteroids) & toxins • Chronic disease (e.g. nephrotic syndrome
Examples of immunosuppressive drugs
• Cyclosporin ; tacrolimus (FK506) ; Rapamycin ; Mycophenolic acid • Anti-TNF therapies: – Blocking mAb – humanized mouse chimera (Infliximab) – Soluble receptor – Fc chimera (Etanercept) • Depleting mAb: – B cells (anti-CD20 – Rituximab) – T cells (anti-CD3 – OKT3) • CLL therapy with fludarabine - induces “AIDS-like” immunosuppressed state
Recurrent Infections That May Not Imply Identifiable Immunodeficiency
• Otitis media (? > 5/yr as cut-off) • UTI • Group A Streptococcus • Staphylococcal furuncles • Dental caries • HSV (labial/genital)
Suspect Immunodeficiency if:
Any patient regardless of age has SPUR which is any of: 1. Severe infection S 2. Persistent infection P 3. Unusual infecting agen U 4. Recurrent infection R
Infections Associated With Anatomical Or Altered Physiology States
Infections Associated With Anatomical Or Altered Physiology States • Allergies (esp. URI) • Cystic fibrosis • Foreign bodies: – Accidental – Iatrogenic • Urinary tract
Indications for immunological evaluation
• ≥2 systemic bacterial infections • ≥3 serious respiratory or other documented focal bacterial infection • Infection at unusual sites e.g. brain, bone or liver abscess • Infections with unusual pathogens • Unusually severe infections with organisms of low virulence• Unusual complications of usual infections • Past surgery for chronic infections: e.g. lobectomy for bronchiectasis or repeated incisions of abscesses • ≥2/12 on antibiotics with little effect • Failure to thrive in infancy • Family history of primary immunodeficiency
how to recognise those with immunodeficiency?
• Nature of the organism (if isolated) often useful – Pneumocystis jirovecii, BCG, disseminated MAI, Aspergillus • Recurrence of infections may be a clue, but does not necessarily imply immunodeficiency – e.g. recurrent UTI usually associated with anatomical abnormalities; recurrent bacterial meningitis may be associated with dural defects or other anatomical defects; recurrent pneumonias and inhaled FB
in B cell deficiency, typical infections:
Bacterial (various)
in T cell deficiency, typical infections are
viral, fungal, intracellular bacteria, if severe - bacterial
in complement deficiencies typical infections
Encapsulated bacteria H influenza, pneumococcus, meningococcus
in phagocyte deficiencies typical infections
Fungi, mycobacteria, salmonella, burholderia
PRIMARY B CELL DISORDERS
• X-linked agammaglobulinemia (XLA) / Bruton’s agammaglobulinemia
– Defect: Btk (src family kinase)
• Common variable immunodeficiency (CVID)
** ** – B cell numbers normal, but do not differentiate to enable antibody production
• Selective IgA deficiency
– 1:700
• Transient hypogammaglobulinaemia of infancy (THI)
– Delay in endogenous Ig production following decline in maternal IgG
• IgG subclass deficiency
• Ig Heavy and Light Chain Deletions
•XLP / Duncan’s disease
– Aberrant response to EBV infection – Defect is in SAP (SLAM-associated protein)
IgA deficiecny prevalence type of diseses and reactions
• 1:700 (Caucasians) • Respiratory or gut infection • Worse if IgG subclass deficiency • Coeliac disease • Major reactions to blood products
IgG Subclass deficiency
• IgG1/G3 response to protein antigens • IgG2 response to polysaccharides produced by splenic T independent B cells • IgG4 no consensus on significance, but isolated case reports; normal range goes down to zero
common variable immunodeficiency is what what is a core feature prevalence FHx contribution typical diseases
• Heterogeneous group of disorders • IgG deficiency is core feature • 20-50 per million • Lifelong illness • FHx of Ab deficiency in 20% • Probably a number of different mechanisms • Recurrent sino-pulmonary infections • Granulomatous disease • Autoimmunity & cytopenias
X linked agammaglobulinaemia what is pathology
• Defect in Bruton’s tyrosine kinase • No heavy chain gene rearrangement • No B cells, lymphoid tissue or immunoglobulin • Presents at 6 months+ • Total absence of Igs and B cells • Antenatal diagnosis possible
infections in Ab deficient states Recurrent: Persistent:”
Recurrent: – Otitis media – Sinusitis (diagnostic pitfalls) – Pneumonia (i.e. LRTI) – Bacteremia (S. pneumo ; H.inf. ; N. mening) • Persistent – Rotavirus – Giardia – Enterovirus
Treatment for Ab deficiency
Immunoglobulin Infusion • Prepared from pooled human plasma • Minimal risk of infection, but screened for known viruses (e.g. Hepatitis C) • Intravenous, or subcutaneous
Primary T cell disorders
• DiGeorge / Thymic Hypoplasia / VCFS
– Presentation similar to SCID
• Hyper IgM Syndrome
– Defect in CD40L (CD154 aka CD40-ligand)
• CD3 Deficiency
• Cytokine Deficiencies
– e.g. inability to make IL-2
• T-cell activation defects
– i.e. signal transduction defects
• CD8 lymphocytopenia
– ZAP-70 deficiency (non-src tyrosine kinase)
IgM syndrome Pathology Features
– Defect in CD40 ligand
– Absent IgG, IgA; normal/↑ IgM
– Antenatal diagnosis possible
– Features of T cell immunodeficiency
– Combination of opportunistic infection and immunoglobulin pattern suggestive of HIMS
– Defect in Ig class switch recombination from IgM (made in a 1˚ immune response) to IgG/A/E (made in a 2˚ immune response)
Pure T cell defects
DiGeorge Syndrome – Branchial arch defects • hypoparathyroidism • aortic arch/truncus defects • thymic aplasia • dysmorphic – Translocation chr 22 – Variable presentation PNP deficiency – Progressive decrease in T cell numbers
Clinical Phenotype Of Severe Combined Immunodeficiency
• Unwell by 3 months of age • Persistent diarrhoea • Failure to thrive • Infections of all types – Common infections – more severe than usual – Unusual & opportunistic infections – Vaccine associated diseases • Unusual skin disease – Graft versus host-like disease because of colonisation of infant’s “empty” bone marrow by maternal lymphocytes • Family history of early infant death
SCID features and types
- “T-B+” – cytokine g chain defect X linked – Jak 3 deficiency AR
- “T-B-” – recombinase deficiency AR – ADA deficiency AR
