Immune Deficiency Disorders

“Nature’s experiments”

connect basic science

and clinical application

“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)

Serum protein electrophoresis:Gamma globulins

XLA involves a block in B cell differentiation

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 Role of CD154 (CD40L) inB Cell Activation

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

Actuarial survival in a cohort of XHIMS patients

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

SCIDS Classification Scheme 2008

Distribution of SCIDS subtypes (Buckley, et al.)

Miscellaneous

Jak3

ADA

Unknown

XSCID

13%

20%7%

15%

45%

Cytokine receptor deficienciesare one cause of SCIDS

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 Molecular and Cellular Basis of Leukocyte Adhesion Deficiency

Integrins

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”)

Family pedigree 1999

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

Fas transmits cell death signal important in lymphocyte homeostasis

The Story of B. F.

• Clinical diagnosis: Autoimmune lymphoproliferative syndrome (ALPS)– Defective Fas expression– Defective lymphocyte apoptosis

• Genetic diagnosis– Mutation in Fas “death domain”

Fas mutation summary in ALPS

TNF Receptor Super Family members

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