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
Who is IgG3 more common for? What other subclass defiencies is it associated with? What is IgG3 responsible for fighting against?
• IgG3 deficiency
– More common in adults
– May occur alone or in combination with other subclass deficiencies, especially IgG1.
– IgG3 is responsible for the immune response against Moraxella catarrhalis and to the M component of Streptococcus pyogenes,
What other subclass deficiencies is IgG4 associated with? What is its prevalence? How does it usually present? What else is it associated with?
• IgG4 deficiency
– IgG4 subclass deficiency has been described alone or associated with • IgG2/IgG4 deficiency • IgA/IgG2/IgG4 deficiency
– IgG4 deficiency is believed to be common in the general population
– Usually asymptomatic
– Symtomatic, recurrent pulmonary infections and bronchiectasis
– Associatioed with
- Ataxia-telangiectasia
- Chronic mucocutaneous candidiasis
- Growth hormone deficiency
- Allergic colitis
- Down’s Syndrome
How are b cell IDSs treated?
- Antibiotics
- IVIG and SCGG therapies
– Dose IVIG 400-800 mg/kg/month
– Reversal of clubbing, coughing, wheezing, improved
PFTs (800 mg/kg IVIG) – Prevention of bronchiectasis – Prevention of ECHO virus infections – Less infection, diarrhea, malaise – Neutropenia improves – Dermatoses improve – eczema, pyoderma – Joint pain, arthritis improves – Weight gain
What are the clinical features of DiGeorge Syndrome or anamoly (DGA)?
• Conotruncal cardiac defects
– Tetralogy of Fallot, Interrupted aortic arch, truncus
arteriosus
• Parathyroid hypoplasia
– Hypocalcemia
• Development
– Speech, motor, cognitive
• Immunodeficiency
– Thymic hypoplasia to aplasia
– Secondary antibody deficiency
• Facies
– Low-set, malformed, posteriorly rotated ears – Micrognathia – Hypertelorism – Small mouth - “Fish mouth” – Bulbous tip of nose
• Palatal anomaly
What genetic defect of DGA associated with? What does it cause?
- Field defect – group of tissue affected as a unit
- Inadequate contribution of neural crest tissues to the 3rd and 4th pharyngeal pouches that leads to defects of mesenchyme
- T-cell Immunodeficiency
– Correlation with amount of thymic tissue present – Hypoplastic in ~95% of patients (Partial DGA) – Aplastic in ~5% of patients
• Extrathymic development of Nonfunctional T cells
(Complete DGA)
- Oligoclonal expression
- Absent in vitro function
– (Collard, Clin Immunol 91:156, 1999)
• B-cell Immunodeficiency – 2nd to T-cell function
What causes X-Linked Hyper-IgM immunodeficiency? What immunologic effects does it have? What infections does it open people up to? What autoimmune disorders is it associated with? How is it treated?
- X-linked
- CD40 ligand (CD40L, CD154) deficiency making it so helper t cells can’t bind to CD40 on b cells and cause them to class switch.
• Combined T- and B-cell PIDD
– T cell antigen-specific function decreased
– IgG, IgA, IgE absent; IgM levels normal or elevated
– Decreased memory B cells
• Neutropenia
– Persistent, transient, cyclic
- Recurrent Infections with pyogenic and opportunistic microorganisms
- Autoimmunity: ITP, hemolytic anemia, hypothyroidism, arthritis
- Treatment – Bone marrow transplantation
How is MHC Class II (bare lymphocyte syndrome) defiency caused? What are its immunological consequences? What are its clinical manifestations? How is it treated?
• Decreased HLA class II expression on B cells, monocytes, activated T cells
• Combined T- and B- cell PIDD – Decreased T cell function – Decreased CD4+ T cells – Decreased IgG, IgA, IgM levels – Decreased antibody responses
• Repeated severe infections
• Progressive liver disease
– Sclerosing cholangitis
• Treatment – Bone marrow transplantation
How are CD3-gamma, delta, epsilon, and zeta deficiencies inherited? What are the immunological results of Delta deficiency? What are the immunological results of the other deficiencies? What are the clinical manifestations? How are they treated?
AR, Chromosome 11
• CD3delta deficiency - T-B+NK+ SCID
• CD3epsilon, CD3gamma, CD3zeta deficiency
– CD3 T cells may be decreased
– Reduced T cell signaling and function
- Repeated severe infections
- Treatment – Bone marrow transplantation
How is Zap-70 deficiency inherited? What is its cuase? What are the immunological results of the SCID phenotype? What are its clinical manifestions? What is the treatment?
- AR, Chromosome 2q12
- Deficiency of cytoplasmic T cell receptor zeta-chain associated protein kinase
• SCID phenotype characterized by absent CD8+ T cells – ALC normal – CD3+, CD4+ T cells normal – T cell function decreased – NK cytotoxicity norma – Serum IgG, IgA, IgM levels – normal – Antibody function decreased
- Recurrent severe infections
- Treatment – Bone marrow transplantation
