Immunology

Question 1

Estimated prevalence of 1ry immunodeficiency (excluding IgA and IgG subclass deficiency)

Answer 1

1 in 100 000

Question 2

Some Secondary Immunodeficiencies

Answer 2

• Infections (e.g. HIV) • Malignancy (and treatment thereof) • Extremes of age • Severe malnutrition • Drugs (e.g. corticosteroids) & toxins • Chronic disease (e.g. nephrotic syndrome

Question 3

Examples of immunosuppressive drugs

Answer 3

• 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

Question 4

Recurrent Infections That May Not Imply Identifiable Immunodeficiency

Answer 4

• Otitis media (? > 5/yr as cut-off) • UTI • Group A Streptococcus • Staphylococcal furuncles • Dental caries • HSV (labial/genital)

Question 5

Suspect Immunodeficiency if:

Answer 5

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

Question 6

Infections Associated With Anatomical Or Altered Physiology States

Answer 6

Infections Associated With Anatomical Or Altered Physiology States • Allergies (esp. URI) • Cystic fibrosis • Foreign bodies: – Accidental – Iatrogenic • Urinary tract

Question 7

Indications for immunological evaluation

Answer 7

• ≥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

Question 8

how to recognise those with immunodeficiency?

Answer 8

• 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

Question 9

in B cell deficiency, typical infections:

Answer 9

Bacterial (various)

Question 10

in T cell deficiency, typical infections are

Answer 10

viral, fungal, intracellular bacteria, if severe - bacterial

Question 11

in complement deficiencies typical infections

Answer 11

Encapsulated bacteria H influenza, pneumococcus, meningococcus

Question 12

in phagocyte deficiencies typical infections

Answer 12

Fungi, mycobacteria, salmonella, burholderia

Question 13

PRIMARY B CELL DISORDERS

Answer 13

• 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)

Question 14

IgA deficiecny prevalence type of diseses and reactions

Answer 14

• 1:700 (Caucasians) • Respiratory or gut infection • Worse if IgG subclass deficiency • Coeliac disease • Major reactions to blood products

Question 15

IgG Subclass deficiency

Answer 15

• 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

Question 16

common variable immunodeficiency is what what is a core feature prevalence FHx contribution typical diseases

Answer 16

• 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

Question 17

X linked agammaglobulinaemia what is pathology

Answer 17

• 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

Question 18

infections in Ab deficient states Recurrent: Persistent:”

Answer 18

Recurrent: – Otitis media – Sinusitis (diagnostic pitfalls) – Pneumonia (i.e. LRTI) – Bacteremia (S. pneumo ; H.inf. ; N. mening) • Persistent – Rotavirus – Giardia – Enterovirus

Question 19

Treatment for Ab deficiency

Answer 19

Immunoglobulin Infusion • Prepared from pooled human plasma • Minimal risk of infection, but screened for known viruses (e.g. Hepatitis C) • Intravenous, or subcutaneous

Question 20

Primary T cell disorders

Answer 20

• 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)

Question 21

IgM syndrome Pathology Features

Answer 21

– 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)

Question 22

Pure T cell defects

Answer 22

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

Question 23

Clinical Phenotype Of Severe Combined Immunodeficiency

Answer 23

• 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

Question 24

SCID features and types

Answer 24

• “T-B+” – cytokine g chain defect X linked – Jak 3 deficiency AR
• “T-B-” – recombinase deficiency AR – ADA deficiency AR

Question 25

►B cells absent • NK cells absent

Answer 25

– Myeloid / Reticular dysgenesis – Adenosine Deaminase (ADA) deficiency

Question 26

►B cells absent • NK cells present

Answer 26

– Recombinase Activating Gene (RAG1 / RAG2) deficiencies – Other Ig / TCR recombination defects

Question 27

►B cells present • NK cells absent

Answer 27

– Common Gamma Chain (gammac) deficiency – JAK3 deficiency

Question 28

►B cells present • NK cells present

Answer 28

– IL-7Ralpha deficiency

Question 29

other combined B/T cell disorders

Answer 29

• Wiskott-Aldrich Syndrome (WAS) – X-linked, defect in WASP. • Ataxia Telangiectasia (AT) – Defect in ATM (DNA-dependent kinase) • Defects in Interferon-g - IL-12 Axis – Systemic BCG, atypical mycobact, Salmonella • Hyper IgE Syndrome – Recurrent Staph abscesses

Question 30

HS Type I

Answer 30

IgE Mast cells degranulate and release histamine, vasoactive mediators, lipid mediators, cytokines Localized clinical response (Atopy) atopic asthma: urticaria (hives) eczema (skin lesions) atopic rhinitis food allergies Systemic clinical response (anaphylaxis) anaphylatic shock

Question 31

HS Type II

Answer 31

IgM, IgG against cell surface or extracellular matrix antigens Osponisation and phagocytosis of cells Complement and Fc-mediated recruitment and activation of leucocytes (neutrophils, macrophages) Abnormalities in receptor functions eg. hormone signalling

Question 32

HS Type III

Answer 32

Complement mediated Complement and Fc-mediated recruitment and activation of leucocytes

Question 33

HS Type IV

Answer 33

CD4+T cells (cytokine mediated) Recruitment and activation of leucocytes