Post on 25-Dec-2015
transcript
“Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of
her workings apart from the beaten path…the study of nature’s experiments and mistakes…may throw a ray of
light into some dark place…”
A. E. Garrod. The Harveian oration on the debt of science to medicine.
Br. J. Med. 2:747, 1924.
Five Stories
Disorder Molecule Defect
XLA Btk Intracellular signaling
XHIM CD154 Intercellular communication
XSCIDS IL2RG Cytokine receptors
LAD CD18 Cell adhesion
ALPS Fas Cell death
The Story of J. L.
• History:– Three episodes of septic arthritis between ages 10-12
months, appropriately treated; multiple episodes of otitis media
• Family history:– Male cousin died suddenly in infancy of unknown
cause
• Laboratory:– Low serum IgM, undetectable IgG and IgA; normal
numbers of peripheral blood T cells, but B cells undetectable
The Story of J. L.
• Clinical diagnosis: – X-linked (Bruton’s) agammaglobulinemia
(XLA)
• Treatment:– Replacement therapy with monthly infusion of
IVIG (pooled human IgG)
XLA is caused by mutations in the btk gene
Positions of individual mutations indicated by colored balls
Implications of identifying and characterizing the btk gene
• Diagnostic testing– Proband– Family, esp. female carriers
• Genotype-phenotype correlation
• Drug therapy
• Gene therapy
The Story of J. L.
• Genetic diagnosis– Point mutation in exon 11 of btk gene
• Genetic screen of potential carriers– Mother confirmed as carrier– Two sisters are not mutation carriers
• Clinical Course:– Age 18 years; no further serious infections;
working on GED, plays football, etc.
The Story of J. H.
• History– Otitis media at 7 months, periorbital cellulitis
at 12 months, pneumonia at 15 months
• Family history– unremarkable
• Laboratory– Normal IgM, low IgG and IgA; normal T and B
cell counts
The Story of J. H.
• Provisional clinical diagnosis– Hypogammaglobulinemia, perhaps common variable
immune deficiency (CVID)
• Treatment– Monthly IVIG
• Clinical course, age 18-36 months– Additional infections: thrush, perirectal abscess,
Candidal esophagitis
• Laboratory– Persistent neutropenia, progressive increase in IgM
The Story of J. H.
• Clinical diagnosis– X-linked hyper-IgM syndrome
• Treatment– Continued IVIG– Addition of three times weekly GM-CSF
• Clinical course– Significant improvement, no additional serious
infections
The Story of J. H.
• Genetic diagnosis: XHIMS1– Defective expression of CD154 on activated T
cells– Mutation in CD154 gene extracellular (TNF-
like) domain– Lost to follow up
Prognosis in XHIMS
• Increased concern about effects of T cell deficiency– Opportunistic viral and fungal infections
• Candidates for stem cell transplant– Reported to also correct neutropenia
• Prospects for gene therapy– Complicated by gene expression pattern
Mutations in autosomal recessive forms of XHIMS
• CD40 (XHIMS2)– Receptor-ligand partner for CD154
• AICD (XHIMS3)– Activation-induced cytidine deaminase– Unexpected association with Ig class
switching through gene-knockout animal model
The Story of F. A.
• History– Three month history of cough; hospitalized
three times for pneumonia with minimal response to therapy
• Family history– Maternal uncle died at age 6 months of
chronic pneumonia
The Story of F. A.
• Laboratory– Lymphopenia with absent T cells, moderate
hypogammaglobulinemia; broncho-alveolar lavage fluid culture positive for parainfluenza virus type III
• Diagnosis– Severe combined immune deficiency
syndrome (SCIDS), probably X-linked
Distribution of SCIDS subtypes (Buckley, et al.)
Miscellaneous
Jak3
ADA
Unknown
XSCID
13%
20%7%
15%
45%
Additional causes of SCIDS
• RAG-1, -2 defects– Involved in TCR, Ig gene rearrangement
• Artemis mutations– Newly discovered gene – Involved in DNA repair
The Story of F. A.
• Genetic diagnosis– X-linked SCIDS: confirmed mutation in
IL2RG/gammac chain
• Course– Died of progressive respiratory failure
• Genetic counseling– Mother and maternal grandmother confirmed
as carriers
Gene Therapy for XSCIDS
• IL2RG a good candidate– Simple gene expression pattern– Corrected cells have growth advantage
• Clinical trial– Gene insertion using retrovirus– 10/10 excellent T cell reconstitution– T cell leukemia in four survivors– Insertion in locus of LMO-1, an important
hematopoietic regulatory gene
The Story of J. B.
• History– Fever, omphalitis and perirectal abscess at
age 3 weeks; cellulitis at i.v. site in foot, leading to osteomyelitis and foot amputation at age 2 months
• Family history– Non-contributory
• Laboratory– Leukocytosis, WBC>60,000/mm3
Pathology Report
• “I don’t know what this is, but…”
• Inflammation in tissue…
• Yet leukocytes restricted to capillaries
The Story of J. B.
• Diagnosis: Leukocyte adhesion deficiency type I– Absent expression of integrin beta2 chain (CD18) by
flow cytometry
• Treatment– Matched, unrelated donor bone marrow transplant
• Course– Long term survivor– Good immune reconstitution, CD18 expression– Severe graft-vs-host disease of the skin
The Story of B. F.
• History– Noted to have enlarged spleen at birth; developed
progressive lymphadenopathy; hemolytic anemia and immune thrombocytopenia
• Family history– Extensive pedigree of similarly affected individuals– Males and females equally affected
• Laboratory– Increased numbers of T cells expressing neither CD4
nor CD8 (“double negatives”)
Patients resemble a strain of mice with similar symptoms
• Splenomegaly, lymphadenopathy
• Autoantibodies
• Double negative T cells
• Mice found to have – defects in cell death pathway known as
apoptosis– spontaneous mutations in either Fas or FasL
The Story of B. F.
• Clinical diagnosis: Autoimmune lymphoproliferative syndrome (ALPS)– Defective Fas expression– Defective lymphocyte apoptosis
• Genetic diagnosis– Mutation in Fas “death domain”
The Story of B. F.
• Survived Hodgkin’s Disease (Lymphoma)
• Treated with standard chemotherapy
• Later developed malignant histiocytosis
• Died August 2007
• Older brother, younger sister both alive and well
Summary
• Basic science increasingly informs clinical medicine– Diagnosis– Treatment– Prognosis
• Discovery leads from bench-to-bedside…and vice versa– Keep your eyes (and minds) open!
Materials from 3rd year clerkship
• Capsule Summary – Clinical signs and symptoms– Laboratory screening– Other pearls
• “Practical Immune Deficiency”– Clinic oriented PowerPoint
• Available as pdf