Primary Immunodeficiency Disease Consortium Conference Report

Thursday, June 1, 2006
San Francisco, CA

The CIS Primary Immunodeficiency Diseases Consortium Conference was held in association with FOCIS recently in San Francisco. This unique forum was chaired by Charlotte Cunningham-Rundles and was sponsored by Talecris, ZLB Behring, The Immune Deficiency Foundation, The Jeffrey Modell Foundation, Baxter and the NIH. The purpose of the CIS Consortium Conference was to provide an opportunity for scientists and physicians working on primary immunodeficiencies to come together for discussion and collaboration on management, diagnosis, and molecular processes related to primary immunodeficiencies. The CIS Consortium Conference was clearly a success, with all levels of training and experience represented and a large contingent of physicians and scientists from abroad. Australia, Italy and Brazil were particularly well represented along with a strong group of Immunologists from the United States.

The conference was divided into several thematic groups of presentations and Jennifer Puck and Jason Cyster were keynote presenters this year. As has been true in this CIS Consortium Conference, several new immunodeficiencies were described. David La Rosa presented a case of a functional NK cell defect which was largely fatal in one kindred. Dr. La Rosa was able to determine that the proband exhibited expansion of a functionally defective CD56 bright population. The defective function was associated with severe herpes viral infections, as is often true for NK cell defects. Raz Somech presented a study of two related patients with SCID, gonadal dysgenesis and a cardiac defect. Both died in infancy of fibrotic lung disease which is not a common feature of immunodeficiencies. Immunologically both appeared to have SCID, with total T cells in the range of 400 cells/mm3, and absent responses to stimulation. Dr. Gatti commented that gonadal dysgenesis is a common feature of DNA repair defects. Elena Perez presented a patient with monosomy of 1p36. This particular syndrome leads to diminished expression of OX40, due to haplosufficiency. The patient suffered from recurrent infections, developmental delay, and some dysmorphic features. The diminished expression of OX40, which activates NF?B and promotes cell survival, offers a potential explanation for this patient's infection pattern. These three oral presentations serve as a reminder that persistence in seeking answers is required for defining immunodeficiencies.

A second theme related to persistence in the field on immunology revolved around the education of primary care providers to recognize signs and symptoms of immunodeficiencies. One of the goals of the CIS Consortium Conference is to promote the education of physicians regarding primary immunodeficiencies. It is a concern that knows no geographic boundaries as several of the presenters were from Brazil. Dewton De Moraes Vasconcelos presented a study that evaluated patients in Brazil who presented with BCGosis, other mycobacterial diseases, cryptococcus, paracoccidiomycosis, or histoplasmosis. Of 29 patients identified with one of these unusual infections, eight were found to have an immunodeficiency. One patient had idiopathic CD4 T cell deficiency and the others had defects in macrophage activation such as IL-12, IL-12 receptor and ?-interferon receptor deficiency. Anete Sevciovic Grumach and Antonio Condino Neto also emphasized identification and education in their studies. Dr. Grumach screened 462 Brazilian patients with unusual infections over five years and found 18 cases of primary immunodeficiencies. She worked closely with Infectious Disease specialists during the recruitment and during the question session pointed out that after working with them for five years, the Infectious Disease specialists now recognize patients at risk for primary immunodeficiencies much better and perform simple screening tests themselves. Antonio Condino Neto focused on identifying features predictive of phagocytic disorders and identified 20 patients with chronic granulomatous disease and 33 patients considered to have abnormal host defense but without explanation currently.

This emphasis on the education of primary care providers will clearly have a significant impact on the early diagnosis and improved management of patients with immunodeficiencies. A necessary and complementing type of study is the further definition of the natural history and phenotypic features of patients with immunodeficiencies. Stuart Turvey discussed the practical application of a clinical test for toll like receptor function. This assay has clear potential for the diagnosis of IRAK4 and NEMO deficiencies. Dr. Turvey cautioned that the assay be reserved for patients with recurrent bacterial infections, as a screen of 50 patients with penumococcal disease was not revealing. Adina Kay Knight presented a compilation of 700 patients enrolled in the Immune Deficiency Foundation common variable immune deficiency registry. The data revealed the anticipated infectious consequences as well as a 21% frequency of autoimmune disease. 13% developed malignancy and approximately half were lymphomas. As the registries mature, similar data should become available for other diseases. USIDNET will soon open the disease specific registries for just this purpose. The registries will help define the unusual manifestations of disease which are often unrecognized. An example of this was the presentation by Oner Ozdemir who presented a case of APECED. This patient presented with Behcet's disease, which is not a presentation most Immunologists would associate with APECED. A study of IL-7 receptor deficient SCID by Charles Haines demonstrated an enormous variety of mutations. The mutations may be found to correlate with phenotype as more data are collected. Kohsuki Imai presented data on 85 patients with hyper IgM syndrome. Approximately half were found to have the X-linked form with mutations in CD40L. Interestingly, two patients were female with skewed X inactivation. The AID form was next most common and only one patient was found to have a mutation in UNG. Disturbingly, there were 19 patients for whom mutations were not identified. It has been felt for some time that there is at least one additional form of hyper IgM. If it is one gene, it will likely account for a substantial fraction of patients.

Three presentations on IPEX served as a powerful reminder that we have much to learn regarding this often fatal disease. Two presentations from the University of Florence by Elenora Gambineri and Rosa Bacchetta served as a warning. Troy Torgerson had presented that of all patients with an IPEX phenotype, only 60% have a mutation in FOXP3. Of the remaining 40%, some have normal levels of FoxP3 protein and some have very low levels. Dr. Gambineri identified a cluster of patients with low levels of FOXP3 mRNA expression and found one mutation that may affect the FOXP3 promoter. Additional studies may reveal other regulatory regions in these patients with low levels of mRNA. Dr. Bacchetta reminded the audience that traditional laboratory studies in IPEX are typically normal. Her studies suggest that there is so far, little correlation of genotype and phenotype in this disease, making therapeutic decisions even more difficult. Both Drs. Torgerson and Bacchetti commented that while stem cell transplantation has been largely unsuccessful using traditional methods, newer strategies for stem cell transplantation have been more successful. In addition, they both mentioned that therapy with rapamycin has been successful.

Improved management for patients is a goal for nearly all Immunologists. In this regard, there were hopeful signs from the presenters. A study by Daniel Bailey of mice with WASP deficiency revealed early onset of anti-nuclear antibodies. This was associated with reduced T cell apoptosis although a causal association was not demonstrated. As autoimmunity is a major source of morbidity and mortality in Wiskott Aldrich syndrome, this may provide a model system in which to study novel interventions. Christopher Fraser presented data on two pediatric patients with complications associated with common variable immunodeficiency who required transplantation. They both received conditioning with fludarabine, melphalan and anti-thymocyte globulin. GVHD prophylaxis consisted of cyclosporine and mycophenylate mofetil. Both patients resolved their autoimmune processes nearly instantly and one patient was able to come off of IVIG. The second patient has been transplanted very recently. Sonal Patel continued the transplantation theme and described two siblings with XSCID who were transplanted rather differently with discordant results in terms of B cell engraftment and IVIG requirement. This was interpreted as a superiority of cord blood transplants over traditional sources of stem cells. A vigorous discussion of the many variables affecting transplant outcome ensued. This talk was followed by a discussion of post-transplant gene therapy for XSCID by Javier Chinen, This NIH salvage protocol has enrolled three patients who receive transduced CD34 stem cells. In spite of large numbers of infused cells, the vector copies per cell were all low and only the patient with over 1% transduced cells peripherally developed any TRECs and naive T cells in the peripheral blood. While somewhat disappointing, this new strategy appeared safe, with no insertions upstream of LMO2. During the discussion of SCID, John Ziegler commented that a recent incidence study of SCID in Australia revealed an incidence of 1:60,000 births. With such a high frequency, definition of optimal therapy is becoming essential.

Another relatively new management strategy is post-natal thymus transplant for DiGeorge syndrome. Two talks by Ivan Chinn and Elizabeth McCarthy served as important reminders that not all presentations are classic and understanding the pathophysiology of the presentation leads to improved management. The patients with atypical DiGeorge syndrome have an expansion of a few T cell clones and present with rash and lymphadenopathy. These oligoclonal T cells do not have normal function and in fact are deleterious. Thymic transplantation for these cases is markedly more difficult and requires very stringent titration of immunosuppressive agents.

The CIS Consortium Conference began and ended with discussion of B cells and there was substantial dialog regarding several of the presentations on antibody deficiencies. Sigune Goldacker presented impressive data from Freiberg on functional subsets of patients with common variable immune deficiency. Patients are often stratified based on the presence of B cells, the ability to produce immunoglobulin in vitro, or the ability to undergo class switching. The in vitro assays are not widely available and there are discrepant systems for categorizing patients. Dr. Goldacker attempted to use the universally available strategy of vaccination to stratify patients. One clear finding was the absence of any response to vaccine in patients with absent B cells, a not unexpected finding. A preserved ability to respond to a polysaccharide vaccine required an intact memory B cell compartment; however, presence of memory B cells does not guarantee a response. Ellen Renner approached a similar question using the neoantigen, ?X 174. She evaluated a broad range of patients with various defects in immunoglobulin production. A combination of flow cytometry for memory B cells and switched memory B cells and responses to ?X 174 identified some characteristics which appeared to be unique to the different forms of hyper IgM. There was variability from patient to patient and additional studies will clarify the diagnostic capabilities of this approach. The last talk on common variable immune deficiency was given by Isabella Quinti. She studied TLR9 signaling in patients with common variable immune deficiency. Memory B cells require TLR9 stimulation for survival and activation. The combination of absent memory B cells, poor responses to polysaccharide antigens and poor in vitro responses to stimulation of TLR9 predicts susceptibility to infection.

The CIS Consortium Conference presented recent exciting data on the molecular bases of primary immunodeficiencies and served to introduce many of us to new immunodeficiencies. The spirited discussion of appropriate management indicates a need for further studies to define a consensus approach for the more common immunodeficiencies and to develop collaborations to support the study of the rarer disorders. The CIS Consortium Conference provided a valuable first step in the long road towards improved understanding.