topic 21 Flashcards
What is the frequency and some general characteristics of SCIDs? How is it inherited?
- Frequency: 1:50,000 Inherited AR or XL
- Combined functional T- and B-cell defects
– NK cell number & function may be decreased
- Paucity of lymphoid tissue
- Absent thymic shadow
What do SCID individuals become infected with?
– Viruses (HSV, V-Z, CMV, EBV, RSV, PI3, adenovrius) – Protozoan (PJP, Cryptosporidium parvum, Toxoplasma gondii )
– Mycobacteria, BCG
– Fungal (Canadia, Aspergillus, Cryptococcus neoformans, Histoplasma capsulatum)
– Bacteria (T-cell), S typhi, L monocytogenes, enteric flora
– Bacteria (B-cell), S pneumoniae, H influenzae, M catarrhalis, P aeruginosa, S aureus, N meningitidis, M pneumoniae
What other symptoms are involved with SCIDs?
• Susceptible to GvHD
– Transfusion
– Maternal T cells transferred in utero
– Omenn syndrome
- Failure to thrive
- Skin
– Eczema
– Alopecia
What do SCIDs look like hematologically?
• Hematologic
– Lymphopenia
– Eosinophilia
– Monocytosis – NK cells – Thrombocytopenia
• Increased B cell malignancies
What are some common features of X linked SCID? What causes it?
• XL T-B+NK- SCID
– Common gamma chain deficiency–>decreased IL-7RA and IL-15RA–>less T and NK cells
• Immunologic – Lymphopenia – Decreased T- and NK cells – Normal B cells – Decreased IgG, IgA, IgM – Decreased antibody titers
What are some clinical features of Adenosine Deaminase deficiency? How are they caused molecularly? What does their immunology look like?
• AR T-B-NK- SCID
• ADA deficiency
– Accumulation of adenosine, 2’-deoxyadenosine and 2’-o-methyladenosine which are toxic to lymphocytes
• Clinical features
– Skeletal abnormalities
– Decreased neurodevelopment
• Immunologic – Profound lymphopenia – Decreased T-, B- NK cells – Decreased IgG, IgA, IgM – Decreased antibody titers
What are clinical features of Purine Nucleoside Phosphorylase Deficiency? What happens molecularly? What are the immunological consequences?
• AR T-B+NK+ SCID
• PNP deficiency
– PNP - metabolizes inosine and guanosine to hypoxanthine in the purine salvage pathway
• Elevated deoxy-GTP (dGTP) and deoxy-ATP levels
– Thymocytes are selectively destroyed by
• Decreased uric acid levels
• Clinical features
– Neurologic symptoms of mental retardation and muscle spasticity
– Autoimmune diseases of AHA, ITP, thyroiditis, neutropenia, SLE
• Immunologic – Lymphopenia – Decreased T cells – Normal B cells and NK cells – Normal IgG, IgA, IgM – Decreased antibody titers
What are the immunological consequences of Rag1/2 deficiency? What do Rag1/2 do?
• AR T-B- SCID
• RAG1/2 deficiency
– Somatic rearrangements of TCR (T cells) and IgH (B cells)
– Recognize recombination signal sequences and introduce a DNA double-stranded break permitting V, D, and J gene rearrangement
• Immunologic – Lymphopenia – Decreased T- and B- cells – Normal NK cells – Agammglobulinemia IgG, IgA, IgM levels – Decreased antibody titers
How is SCID treated?
- Newborn screening for T cell PIDD
- Bone marrow transplantation
- Enzyme replacement (PEG-ADA)
- Gene therapy (Common chain, ADA, WAS)
- IVIG
- Avoidance live viral vaccines
- Irradiation blood products
- Prophylactic antibiotics
What microbe infections do people with B cell IDS get? What clinical manifestations are there?
- Bacterial infections with polysaccharide encapsulated bacteria, eg S. pneumoniae, H. influenzae, M. catarrhalis , S. pyogenes, P. aeurginosa, S. aureus, M. pneumoniae, N. meningitidis
- Other infections – Enteroviruses, G. lambli
- Recurrent upper and lower respiratory infections
- Otitis media: ≥4 (≥8) within 1 year; mastoiditis
- Sinusitis: ≥2 within 1 year
- **Pneumonia: ≥2 within 1 year; bronchiectasis
- Abscesses: Recurrent, deep skin or organ abscesses
- *****Deep seated infections: ≥2 in life, such as meningitis, sepsis or osteomyelitis
- Vaccine failure: Invasive infection with S. pneumoniae, H. influenzae type B, MCV4
- Response to antibiotics
- ≥2 months with little effect
- *****Need for iv antibiotics to clear infection
What are other signs of B cell IDS?
- Paucity of lymphoid tissue - lymph nodes, tonsils and adenoids
- Immune cytopenias – ITP, AHA, Evan’s syndrome
- Autoimmunity - RA, SLE, chronic urticaria
• Pulmonary – Pneumonia – Reactive airway disease – asthma – Bronchiectasis – Granulomatous interstitial lung disease – Lymphoid interstitial lung disease
- Gastrointestinal
- Giardia lamblia
- Sprue-like enterocolitis
- Granulomatous colitis, enterocolitis
- Intestinal lymphoid nodular hyperplasia
- Malignancies
- Lymphoreticular
- Gastric carcinoma
• Family history
What causes X linked agammaglobulinemia? What immune deficiencies does it cause? What infections does it cause? What other effects does it have?
• BTK mutation
• Immune deficiency
– Decrease IgG, ↓ IgA, ↓ IgM
– Decreased antibodies to protein and polysaccharide antigens
– Absent mature B-cells
• Infections
– Onset of symptoms in 75% by 12 months old
– Bacterial sinopulmonary, sepsis, meningitis
– Susceptibility to ECHO viruses
- Arthritis
- Autoimmunity – not increased
- Malignancies
What is the prevalence of common variable immunodefiencies? Clinical features? Immune deficiencies? Onset of disease?
- Prevalence – 1:10,000 – 100,000
- Clinical features
– Infections – Cytopenias, AHA, ITP – Autoimmune disorders, SLE, RA – GLILD, LIP – IBD – Lymphoma, gastric carcinoma
• Immune deficiency
– Decreased IgG, IgA, ± IgM
– Decreased antibody titers to protein and polysaccharide antigens
– Mature B-cells present
• Decreased memory and switched B cells
• Onset of disease
– 1-5 years old
– 16-20 years old
What does IgG1 subclass deficiency usually result in? What is it classified as?
– IgG1 subclass deficiency usually results in generalized hypogammaglobulinemia
– Classified as CVID
Who is IgG2 defiency more common for? What is it associated with? What happens to it with time? What is IgG2’s primary response?
• IgG2 deficiency
– More common in children than adults
– May be isolated
– Associated with IgG4 and/or IgA deficiency
– IgG2 deficiency may resolve with age, or in a minority of patients, may progress to CVID
– Principal subclass response to polysaccharide antigens, eg Streptococcus pneumoniae
