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This study documents the occurrence of selective IgA deficiency in the dog. This is a unique spontaneous animal model with clinical and immunologic findings similar to that of selective IgA deficiency in humans, the most common human primary immunodeficiency. The disease in the dog is characterized by chronic, recurrent respiratory infections and dermatitis, low concentrations of serum IgA, normal concentrations of serum IgG and IgM, normal T-cell function as measured by lymphocyte transformation tests, the presence of autoantibodies, and a defect in the maturation or terminal differentiation of IgA B cells into IgA-secreting plasma cells.
We report a young child with hypoplastic anemia and antibody deficiency with normal serum immunoglobulin levels. Studies of antibody responses to bacteriophage phi X 174 revealed an amnestic response but was predominantly limited to IgM. A similar response was observed following booster tetanus toxoid immunization. Analysis of in vitro pokeweed mitogen-induced immunoglobulin synthesis by the patient's B cells suggested an intrinsic B-cell defect.
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Patients with common variable immunodeficiency (CVI) have decreased immunoglobulin levels resulting in frequent infections. Although previous studies have suggested that the B cell is intrinsically defective, numerous T cell deficiencies, including reduced interleukin-2 (IL-2) production, have been described. Since the addition of T cell cytokines to CVI B cells can increase Ig secretion in vitro, hypogammaglobulinemia in CVI may be due to defective T cell functions. To assess this possibility directly, we treated five CVI patients intravenously with a new biologic, human recombinant IL-2 conjugated to polyethylene glycol. Doses were 250,000 IU/m2 weekly for Weeks 1-4, 500,000 IU/m2 for Weeks 5-8, and 10(6) IU/m2 for Weeks 9-12. During and after treatment, B cells of all patients secreted 10- to 1000-fold more Ig in vitro. There was also a striking improvement in T cell helper activity since T cells of treated patients could induce 10- to 10,000-fold increases in Ig secretion by B cells from normal donors. No increase was seen in serum Igs during the study, but the anti-tetanus antibody of the IgG isotype could be detected in cell culture supernatants. Whether the effects of infused polyethylene glycol IL-2 are mediated through T or B cells, or both, is still unknown. However, these data reinforce the concept that CVI B cells may be competent, but, lacking essential T cell growth factors, in vivo maturation to Ig production does not occur.
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Hairy-cell leukemia is an unusual chronic lymphoid leukemia with distinctive clinical and pathological features. The management of this disorder has been revolutionized in the last decade with the discovery of the efficacy of alpha interferon and the inhibitors of adenosine metabolism, deoxycoformycin and chlorodeoxyadenosine. The best treatment protocol for hairy-cell leukemia has not yet been defined. Patients may still die from their disease, particularly in the early phases of treatment. Conversely, some patients appear not to require treatment and others respond well to splenectomy and need no further therapy. An individualized clinical approach is recommended, with a role for splenectomy in the patient with cytopenia and a relatively low number of hairy cells in the bone marrow. The first line drug treatment remains interferon alpha given for 12-18 months, following which the patient is observed for clinical relapse. Deoxycoformycin remains a useful experimental agent but cannot be recommended for routine clinical use until issues of long term toxicity are resolved. Chlorodeoxyadenosine is a very promising experimental drug, but confirmation of the early data in larger group trials is required. Similarly the adjunctive use of granulocyte colony stimulating factor appears useful, but will need further study in larger groups of patients. There is little or no role for alkylating agents or more intensive chemotherapy in the modern management of hairy-cell leukemia.
Recent progress on the cellular and molecular basis for T cell dysfunction in aged mice is reviewed, with emphasis on defects in calcium signal generation and protein kinase function. The accumulation in older mice of memory T cells at the expense of naive T cells seems to account for most of the decline in the proportion of cells that can secrete or respond to interleukin 2. Memory T cells in mice of any age have an intrinsic resistance to increases in cytoplasmic free calcium ion concentration, which in turn interferes with their responses to polyclonal activators. T cells from old mice also exhibit declines both in serine/threonine and in tyrosine-specific protein kinase signals after activation by either receptor-dependent or receptor-independent agonists.
Natural killer (NK) cell activity, a component of the immune surveillance system, was compared in women whose husbands had recently died with that found in age-matched women who had not experienced recent adverse life events. Bereaved women had significantly lower NK activity than women whose husbands were healthy. In a second study, depressive symptoms and NK activity were measured longitudinally in women before and after the death of their husbands. Our results suggest that depressive symptoms, not merely the death of the spouse, are related to a reduction in NK activity during bereavement.
Although idiopathic humoral immunodeficiencies are arbitrarily classified into specific antibody deficiency (SAD) or common variable immunodeficiency (CVID), this distinction does not accurately predict the risk of the bronchiectasis, one of the major long-term clinical complications in these patients. In this study, clinical complications were compared with laboratory markers of cellular and humoral immunity in fifty-five consecutive patients (27 children and 28 adults) attending regional immunology clinics in Manchester, United Kingdom. Reduced CD19(+)CD27(+)IgD(-) B cell percentage but not serum immunoglobulin levels or classification of patients into SAD and CVID was associated with a significantly higher prevalence of bronchiectasis (OR 0.4 (0.2-0.8), P = 0.001), splenomegaly (OR 0.2 (0.1-0.5), P = 0.001) and autoimmunity (OR 0.4 (0.2-0.7), P = 0.003). We conclude that in patients with idiopathic humoral immunodeficiencies assessment of B cell switching more accurately predicts clinical prognosis than either classification of patients into SAD and CVID or serum immunoglobulin concentrations.
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A previously well 34-month-old male presenting with fever, skin rash, and arthralgias was found to lack C3 by immunochemical (undetectable) and hemolytic (1% normal) assays. No infectious agent could be demonstrated. Protein levels of Clq. C4, C5, properdin, and C3b-INA and hemolytic activities of complement components C1 to C9 except C3 were normal or elevated; total hemolytic complement activity was 13% of normal and was reconstituted by purified C3. Properdin factor B was 702 (normal 175 to 275) mug/ml, and was not cleaver upon addition of zymosan or cobra venom factor. The serum had normal immune adherence activity, but was deficient in ability to opsonize Candida albicans for uptake and Escherichia coli for killing by neurophils, generate neutrophil chemotactic factors and inhibit the growth of E. coli; these activities were restored by purified C3. A transfusion of 320 ml 1-hour-old normal whole blood on the fifty-second day resulted in transitory elevation of the C3 level to 25 mg/dl with a fall-off (approximately 2 1/2% per hour) to undetectable levels by 69 hours; it was followed by disappearance of the skin rash and arthralgias and return to normal of the previously elevated temperature and CRP levels. C3 levels in family members (seven of 24 half-normal), lack of anti-C3 activity, normal C3b-INA levels and a normal rate of catabolism of transfused C3 indicated that the deficiency was inherited with autosomal codominance and involved decreased synthesis of C3. Thus, this child is a unique individual with inherited C3 deficiency presenting with absence of repeated infections, whose symptoms of fever, skin rash, and arthralgia were abated by whole blood transfusion.
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The field of clinical immunology is advancing rapidly and will continue to grow and benefit from the knowledge gained in different areas of basic immunology. The diagnosis and evaluation of a child with a suspected primary immune defect can be a challenging task that should be done carefully using the best available laboratory resources. Simple laboratory screening tests, available to most pediatricians, can be done initially and will provide an idea of the level of general immune competence. Referral for a more detailed evaluation should be made in selected cases. A basic understanding of the tests used in immune evaluation, as well as the fact that the results may be affected by multiple variables, is important. Of equal significance is the interaction of the physician with the laboratory in which the samples will be analyzed. Proper sample collection and handling as well as prompt processing by the laboratory are crucial. Equally important is the physician's interpretation of results in the context of the pediatric population. Tests like lymphocyte studies, WBC studies, immunoglobulin subclasses, response to antigenic challenge, and certain complement assays require a higher degree of expertise and should only be sent to laboratories with experience in performing them. Physicians need to gain confidence in the power of diagnosis that the immunology laboratory brings to their patients.
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4 young children with active cytomegalovirus (C.M.V.) infection were found, by an in-vitro lymphocyte-proliferation assay, to have a C.M.V.-specific cell-mediated immune defect. These children had antibodies to C.M.V. and were actively shedding C.M.V. in the urine when studied. Their general cellular immune responses were intact, with normal numbers of T lymphocytes and normal in-vitro responses to mitogens and at least one antigen. 3 of the 4 mothers studied shortly after delivery had decreased cell-mediated immunity to C.M.V. These findings suggest that an antigen-specific immune defect facilitates transmission of virus from mother to infant and permits persistence of viral replication in the offspring.
BALB/c and C57BL/6 mice were infected with murine cytomegalovirus (MCMV). On day 4 or 12 of the infection, the animals were immunized with SRBC (T-dependent), TNP-Ficoll (T-independent) and standard poliovirus. The adverse effect of the virus infection on humoral immune responses was limited to animals immunized on day 4; while anti-SRBC antibody formation was severely depressed in both mouse strains, reduced plaque forming cells to TNP-Ficoll were registered only in BALB/c mice. Antibodies to poliovirus were depressed in both strains, although to a lesser degree in C57Bl/6 than in BALB/c mice. Anti-SRBC B cell memory was found to be affected by MCMV infection. These results are interpreted to mean that T-dependent and -independent antigens may be handled differently by the two mouse strains tested.