Hereditary Immune Deficiency Diseases

Question 1

What is the clinical phenotype of granulocyte deficiencies?

Answer 1

• skin, lymph node, or deep tissue infections, esp with S. aureus, Serratia (gram - organisms), and Aspergillus
• hepatosplenomegaly
• lymphadenopathy
• mechanism: ubiquitous organisms, specific antibody not required for opsonization, innate responses essential-need neutrophils

Question 2

What is an example of granulocyte deficiency?

Answer 2

Chronic granulomatous disease

• x linked recessive mainly
• recurrent infections by staph aureus, serrate, candida, aspergillus
• CBC looks normal, normal neutrophil morphology, phagocytosis and chemotaxis
• however no bactericidal activity by neutrophils due to NADPH oxidase (Phox) dysfunction
• Diagnosis: via Phox activity
• usually in kids < 1 years old

Question 3

What is the clinical phenotype of hyposplenism?

Answer 3

• primary or secondary, secondary can be due to sickle cell
• recurrent bacterial sepsis due to S. pneumoniae, H. influenzae, type b (encapsulated organisms)
• Mechanism: encapsulated organisms need antibody and complement opsonization
• spleen has unique ability to generate very rapid natural antibodies via B cells, IgM, to blood borne microbes

Question 4

What are the clinical phenotypes of T cell deficiencies?

Answer 4

• DiGeorge Anomaly phenotype
• Opportunistic infections: viral, fungal, mycobacterial
• GI symptoms
• Oral candidiasis
• hepatosplenomegaly/lymphadenopathy
• severe seborrhea like dermatitis
• mechanisms: multiple mutations in t cell maturation and signaling pathways, deficient t cell mediated immune response, deficient B cell help

Question 5

What is DiGeorge syndrome? What is the phenotype?

Answer 5

• autosomal dominant, associated with del22q11.2
• variable spectrum of organ system involvement:
• -craniofacial dysmorphisms
• -cardiovascular: conotruncal malformations
• -parathyroid: hypocalcemia
• -thymic: t cell deficiency
• T cell deficiency varies from asymptomatic to thymic a genesis with absence of t cells

Question 6

What is severe combined immune deficiency? (SCID)

Answer 6

• clinical syndrome/phenotype characterized by infections which reflect combined deficiencies/dysfunctions of T-cells and B-cells
• Maturation defects: e.g. DiGeorge with absent thymus
• Signaling defects: ineffective TCR fxn

Question 7

What is the clinical phenotype of B-cell deficiencies?

Answer 7

• Respiratory tract infection with usual bacterial pathogens
• GI symptoms
• Granulocytopenia or JRA like arthritis as presenting signs
• Mechanism: multiple mutations in B cell maturation and signaling, deficient antigen specific antibody required for efficient opsonization of encapsulated organisms, deficiency may be systemic or local

Question 8

What is X-linked Aggamaglobulinemia (XLA)?

Answer 8

• B cell maturation genetic defect
• mutations in Bruton Tyrosine Kinase results in maturation block beyond pre-B cells
• absent mature B cells
• Absent IgM, IgG, and IgA antibodies
• normal T cell number and function

Question 9

What is selective IgA deficiency?

Answer 9

• Most common primary immune deficiency
• variable genetic patterns
• likely a signaling defect resulting in failure of isotope switch to IgA
• clinical spectrum: asymptomatic mostly, atopic disease, recurrent infections, autoimmune disorders
• IgG defends lower respiratory tract, so infections in upper resp tract

Question 10

What is common variable immune deficiency?

Answer 10

• Group of immunodeficiencies with:
• hypogammaglobulinemia
• recurrent bacterial infections
• impaired antigen specific antibody responses
• normal number of B cells

Question 11

What is a primary immune deficiency?

Answer 11

-documented or presumed genetic mutations in immune response pathways

Question 12

What is the SCID newborn screening program in CA?

Answer 12

• all newborns screened without needing consent
• TREC is quantified by PCR (TREC are by products of TCR gene rearrangement and is surrogate for number of t cells)
• abnormal screens are sent for CBC+diff and lymphocytes subset analysis by flow cytometry
• Survival improved if BMT/HSCT done before complicating infections

Question 13

What are therapies for immune deficiency disorders?

Answer 13

1. correct secondary pathology
   - treat infection, malnutrition
2. enhance/support existing immune responses
   - interleukins
   - interferon gamma
3. replacement of missing/dysfunctional factors
   - HSC or bone marrow transplant
   - IVIG
   - PEG
4. correction of primary genetic defect-gene therapy