Biomedical subjects
Publications and source records attributed to C M Roifman.
Chronic mucocutaneous candidiasis is a heterogenous group of disorders, associated with a variety of autoimmune disorders and a broad spectrum of immune aberrations. We describe 2 patients with chronic mucocutaneous candidiasis who had cerebrovascular disease with severe neurologic sequelae. Results of angiography of cerebral vessels and brain biopsy in one were consistent with the diagnosis of cerebral vasculitis.
A 10-year prospective cohort study followed the evolution of antibodies in children less than 4 years of age with hypogammaglobulinemia. Three patterns were identified: in group 1, immunoglobulins and antibody production normalized;iin group 2, patients continued to have low IgG levels; and in group 3, IgG levels normalized but antibody levels were transient. Statistical analysis showed that invasive infection or low tetanus antibodies at presentation were associated with the development of significant humoral immunodeficiency.
Eosinophils contribute to the inflammatory process in a variety of chronic inflammatory bowel diseases. Ketotifen is beneficial in experimental models of colitis and in patients with eosinophilic gastroenteritis. Therefore, we investigated the efficacy of ketotifen therapy for the treatment of active ulcerative colitis. Children with newly or previously diagnosed ulcerative colitis with mild-moderate disease activity were treated with ketotifen at a dosage of 4 mg daily for eight weeks. Efficacy was determined by a physician disease severity index and by endoscopic and histologic examinations. Ten patients were enrolled. Symptoms improved in four patients and resolved completely in one patient. There was endoscopic improvement in three patients and histologic improvement in one. Increased eosinophils on rectal biopsy at entry were present in two of the responders. Five patients withdrew due to a lack of symptomatic improvement. No adverse events were identified. Low-dose ketotifen offers a limited therapeutic advantage in active ulcerative colitis that may be enhanced in the subgroup of patients with a high eosinophil count in the colonic mucosa. Further study of therapeutic efficacy with increased dosages of the mast cell stabilizer for acute and maintenance therapy is warranted.
One of the most common human immunodeficiencies is an X-linked condition arising from mutations of the gamma subunit of the interleukin-2 receptor (IL-2Rgamma). The IL-2Rgamma protein is one chain of the heterotrimeric (alpha, beta, gamma) IL-2 receptor, but also participates in the formation of the IL-4, 7, 9, and 15 receptor complexes. The diagnosis of X-linked SCID is usually relatively simple due to the distinctive immunological presentation; IL-2Rgamma-deficient patients typically lacking mature T lymphocytes (T-B+). However, it is becoming clear that this merely represents one extreme of a potential range of clinical presentations. We describe here a novel mutation of the human IL-2Rgamma chain (R222C) resulting in an unusual immunological phenotype. Although clinically immunodeficient, this patient has normal numbers of peripheral T and B cells, responds normally to mitogenic stimuli, and unusually, has a normal thymus gland. This IL-2Rgamma mutation is distinctive in that the protein is sufficiently stable to be expressed at the cell surface. While the T cell receptor repertoire appears complete, suggesting normal T cell differentiation occurs, patient T cells demonstrate a reduced ability to bind IL-2 and this appears sufficient to cause a deficiency in their ability to participate in antigenic responses. Early clinical recognition of this phenotype is critical as a delay in diagnosis may result in a fatal infection.
IL-7 is central to T cell development, inducing proliferation and differentiation, but the signal transduction mechanisms by which it accomplishes these functions are poorly understood. We demonstrate that, in addition to activation of the Jak1 and Jak3 kinases, IL-7 stimulation of human thymocytes results in the rapid tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-2 proteins. We show that the Jak1 and Jak3 kinases are associated with both IRS-1 and IRS-2 in thymocytes. However, the pool of Jak3 kinase associated with IRS-1 appears to be preferentially activated upon IL-7 stimulation. We further demonstrate that the 160- to 185-kDa IRS proteins associate with the p85 regulatory subunit of phosphatidylinositol 3 (PI3)-kinase in an IL-7-dependent manner, although significant differences were evident in the levels of PI3-kinase activity associating with each IRS protein. Although IRS-1 displays a higher degree of basal association, IL-7 induces a much greater increase in the activity associated with IRS-2. Lastly, we show that the PI3-kinase activity associated with the IRS proteins appears to be distinct from that bound to the IL-7R, suggesting the existence of separately regulated pools of PI3-kinase activity. This study suggests that IL-7R signaling diverges at the level of the IRS-1 and IRS-2 proteins, possibly with the two branches regulated by Jak3 and Jak1 activities, respectively.
Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.
OBJECTIVE: To assess the value of high-resolution computed tomography (HRCT) in determining the extent and significance of lung disease in children with antibody deficiency states. MATERIALS AND METHODS: Seventy HRCT scans performed on 37 children with various antibody deficiency disorders over a 5-year period were retrospectively scored using a previously described demerit scoring system (0-25 with 0 = worst, 25 = best). Points are subtracted from 25 with increasing severity of disease. The potential correlations between CT scores and clinical factors, including age at diagnosis, age at CT, type of immunoglobulin deficiency, length of respiratory symptoms before diagnosis, number of pneumonias before diagnosis, type, length and success of therapy, patient compliance and pulmonary function tests (PFTs), were assessed. RESULTS: Of the 37 children, a demonstrated 22 abnormal scans (CT score < or = 22). All nine demonstrated bronchiectasis with a lower lobe and right middle lobe predominance. Statistically significant correlations were seen between severity of lung disease (CT score) and length of respiratory symptoms before diagnosis (p = 0.01), success of therapy (P = 0.001) and PFTs (P = 0.0008). Of seven children who were followed with repeated scans, 4 of the 7 demonstrated CT scores which improved on high-dose intravenous immunoglobulin replacement therapy. CONCLUSION: HRCT is a useful adjunct to demonstrate the extent and severity of lung disease at diagnosis and during therapy. Correlation with clinical factors suggests a higher risk group needing more aggressive management.
The effect of high-dose intravenous immune globulins was evaluated in an open prospective multicenter study of 26 children with severe Guillain-Barré syndrome. They presented with mild to moderate flaccid weakness of extremities, with cranial nerve involvement (20) and sensory impairment (22). All children rapidly deteriorated in 2-16 days (mean 6) to become bedridden, and 2 children also developed respiratory failure requiring artificial ventilation (Disability Grading Scale 4-5). Immune globulins were then administered at a total dose of 2 gm/kg, on 2 consecutive days, without adverse effects requiring discontinuation of therapy. Marked and rapid improvement was noted in 25 children, who improved by 1 to 2 Disability Grade Scales < or = 2 weeks after the infusion. Twenty were able to walk independently by 1 week, and 1 could be weaned off a ventilator. Eighteen children recovered by 2 weeks. The rest recuperated in a period of four months, including a child who was artificially ventilated for 4 weeks. The uniform rapid improvement and recovery associated with immune globulins contrasts with the slow recovery course in severe natural cases. We conclude that immune globulins are effective and safe in severe childhood-onset Guillain-Barré syndrome and therefore may serve as the initial treatment of choice.
Short-term deferiprone may reduce body iron in some patients with thalassaemia major. Concerns regarding potential immunosuppressive effects of deferiprone have been raised from results of animal studies and case reports in humans. We studied immune function in 57 thalassaemia patients: 36 treated with deferiprone (L1; CP020) and 21 treated with desferrioxamine (DFO). Circulating B lymphocytes were increased in all patient groups. No differences were detected between treatment groups in percentages of circulating lymphocytes, concentrations of IgG, IgM or IgA, specific antibody titres, complement levels, or in vitro lymphocyte proliferation. No clinically important infections were observed in any patient. These data suggest that no clinical or laboratory changes consistent with immuno-suppression or immunodeficiency are observed during deferiprone therapy.
Although expression of the Jak3 tyrosine kinase in T lymphocytes has been thought to be restricted to mature, activated cells, mutations of Jak3 can lead to the development of a human severe combined immunodeficiency (SCID) characterized by an absence of peripheral T lymphocytes. We therefore examined in detail the expression of Jak3 throughout human T cell differentiation and show that Jak3 is in fact present throughout the entire developmental process, with high levels expressed in thymocytes. Jak3 is highly expressed in double negative (CD4- CD8-) cells, one of the earliest stages of thymocyte differentiation, and can be activated via the IL-7 receptor. IL-7 is known to stimulate thymocyte proliferation and initiate re-arrangement of the T cell receptor (TCR) beta gene, suggesting that the failure of mutated Jak3 proteins to transduce this signal may be responsible for failures in T cell development. While Jak3 SCID patients possess mature peripheral B cells, we demonstrate that the Jak3 tyrosine kinase is also expressed in human pre-B cells and can be activated by the pre-B cell growth factor IL-7.
Acute lymphoblastic leukaemia (ALL) is the most common cancer of childhood. Despite the progress achieved in its treatment, 20% of cases relapse and no longer respond to chemotherapy. The most common phenotype of ALL cells share surface antigens with very early precursors of B cells and are therefore believed to originate from this lineage. Characterization of the growth requirement of ALL cells indicated that they were dependent on various cytokines, suggesting paracrine and/or autocrine growth regulation. Because many cytokines induce tyrosine phosphorylation in lymphoid progenitor cells, and constitutive tyrosine phosphorylation is commonly observed in B-lineage leukaemias, attempts have been made to develop protein tyrosine kinase (PTK) blockers of leukaemia cell growth. Here we show that leukaemic cells from patients in relapse have constitutively activated Jak-2 PTK. Inhibition of Jak-2 activity by a specific tyrosine kinase blocker, AG-490, selectively blocks leukaemic cell growth in vitro and in vivo by inducing programmed cell death, with no deleterious effect on normal haematopoiesis.
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The interleukin-7 (IL-7) receptor is expressed throughout T-cell differentiation and, although lacking a tyrosine kinase domain, mediates tyrosine phosphorylation in T cells. We have identified IL-7-induced activation of three cyoplasmic tyrosine kinases in T cells, Jak1, Jak3, and the src-like kinase p56lck. Many members of the cytokine receptor superfamily activate the Jak protein tyrosine kinase family, with resultant phosphorylation of the Stat transcriptional activator factors. We describe here a novel function of the Jak kinases, because Jak kinase activity is not only required for Stat activation but also for P13 kinase response to IL-7 in human T cells. We show that IL-7 receptor-mediated Jak activation can occur independently of p56lck activity. IL-7-induced P13 kinase activation, mediated by tyrosine phosphorylation of the P13 kinase p85 subunit, is essential to the IL-7 proliferative signal and also occurs in the absence of src family kinase activity. Jak3 is found associated with the p85 subunit of P13 kinase in an IL-7-responsive manner in T cells and appears to regulate IL-7-induced P13 kinase activation by mediating tyrosine phosphorylation of the p85 subunit. Specific inhibition of IL-7-induced Jak kinase activity ablates p85 tyrosine phosphorylation, subsequent P13 kinase activation, and, ultimately, proliferation. The ability to regulate P13 kinase activity indicates a more generalized role for the Jak family than activation of gene transcription via the Stat family in cytokine receptor signal transduction.
Traditional treatment of dermatomyositis often fails and is associated with severe side effects, especially in children. Similarly, some patients with systemic juvenile rheumatoid arthritis continue to develop crippling arthritis despite the currently used modalities of therapy. We have used monthly infusions of intravenous immune globulin (2 g/kg/month) in patients with dermatomyositis or systemic juvenile rheumatoid arthritis who have not responded to traditional treatment. We show that intravenous immune globulin is beneficial in improving muscle strength and skin manifestations of dermatomyositis. In a similar fashion, intravenous immune globulin infusions were very effective in ameliorating systemic manifestations of systemic juvenile rheumatoid arthritis but less effective in controlling long-lasting arthritis (more than 1 year). We established prognostic criteria early after disease onset which predict the development of severe joint disease and should help in patient selection for future studies.
We have previously described a new type of selective T-cell deficiency characterized by persistent infections reminiscent of severe combined immunodeficiency. We show here that selective T-cell deficiency patients carry a mutation of zap-70 protein tyrosine kinase, resulting in a loss of the activity of this kinase. The thymus of zap-70(-1-1) patients shows the presence of CD4CD8 double-positive cells in the cortex, however, only CD4, and not CD8, single-positive cells are present in the medulla. Peripheral CD4+ T cells from the zap-70(-1-1) patients exhibit markedly reduced tyrosine phosphorylation, fail to produce interleukin-2, and do not proliferate in response to T-cell receptor stimulation by mitogens or antigens. Thus zap-70 kinase appears to be indispensable for the development of CD8 single-positive T cells as well as for the signal transduction and function of single-positive CD4 T cells.
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Growth and maturation of B lymphocytes from stem cells require a series of complex processes that are dependent at least in part on growth factors. Uncontrolled expression of receptors from these early growth factors may contribute to a leukaemogenesis of such early B cell progenitors. We show here that early pre-pre-B cells, but not mature B cells, express the PDGF receptor-beta (PDGFR-beta). These receptors contain a protein tyrosine kinase domain which is activated upon ligation with PDGF in pre-pre-B cells. Further, pre-pre-B leukaemia cells seem to express more PDGFR-beta compared with their normal counterparts, suggesting a role for these receptors in growth promotion of leukaemia cells.
We have previously described a new type of selective T-cell deficiency (STD) characterized by persistent infections reminiscent of severe combined immunodeficiency (SCID). We show here that STD patients carry a mutation of zap-70 resulting in a loss of the activity of this kinase. The thymus of zap-70-/- patients shows the presence of CD4CD8 double positive cells in the cortex, however, only CD4 but not CD8 single positive cells are present in the medulla. Peripheral CD4+ T cells from the zap-70-/- exhibit markedly reduced tyrosine phosphorylation, fail to produce IL-2, and do not proliferate in response to TCR stimulation by mitogens or antigens. Thus Zap-70 kinase appears to be indispensable for the development of CD8 single positive T cells as well as for signal transduction and function of single positive CD4 T cells.