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The immunodeficiency, at present an important complex of research, can be classified in 4 main groups. Primary forms can be separated from secondary ones, a third group of interactional type from a fourth one of compensatory character. We suggest a new classification based on a common point of view, which avoids terms as "common variable immunodeficiency" and allows corrections by the results of further research.
The proportion of T-cell subsets was normal in all patients with X-linked agammaglobulinemia except for an 8-month patient who showed a decrease in OKT8+ T-cell population. In two patients with hypogammaglobulinemia with IgM production, T-cell subsets were normal in distribution and the patients' B cells produced only IgM in culture with autologous T cells. A patient with common variable immunodeficiency showed no imbalance in distribution of T-cell subsets. Imbalance of regulatory T-cell subsets was found in a patient with DiGeorge syndrome and severe combined immunodeficiency.
BACKGROUND: Intravenous immunoglobulins (IVIG) have usually been administered for replacement therapy of humoral immunodeficiencies, but their use in treating other disorders with an immune pathogenesis is increasing. The exact mechanism of action by which IVIG are of benefit in such diseases is complex and only partly understood. One of the proposed mechanisms of action is the modulation of cytokine release. METHODS: We selected 29 patients with primary hypogammaglobulinemia (common variable immunodeficiency), receiving long-term substitutive therapy with IVIG, and 14 healthy blood donors as a control group. Blood samples were then taken before and 1 hour after finishing the IVIG infusion. Only one blood sample was obtained from the healthy controls. The cytokines studied were interleukin (IL)-1 beta, IL-1 receptor antagonist (IL-1Ra), IL-2, IL-6, IL-8, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. RESULTS: Patients with primary hypogammaglobulinemia showed significantly higher serum levels of IL-6, IL-8, IL-1Ra, and TNF alpha than healthy controls. IVIG infusion significantly increased serum concentration levels of IL-6, IL-8, IL-1Ra, and TNF alpha. No significant variation was observed in serum levels of IL-beta, IFN gamma, or IL-2 after IVIG infusion. Age, IVIG commercial preparation, and IVIG dose did not influence cytokine serum levels. Moreover, a significant correlation was observed between serum level variations of IL-1Ra and TNF alpha, as well as an associative trend between maximum changes in IL-6 and IL-8 concentrations. CONCLUSIONS: IVIG administration significantly alters the serum pattern of selected cytokines, which might explain, at least in part, the mechanism of action of IVIG in autoimmune or inflammatory disorders.
Peripheral blood T and non-T lymphoid cells were examined in 31 patients with a variety of primary immmunodeficiencies for their locomotor activity toward casein and endotoxin-activated serum. T cells from 1 and non-T cells from 2 of 7 patients with Bruton type agammaglobulinemia had poor locomotor activity in this system. Both T and non-T lymphoid cells from all patients with common variable immunodeficiency disease had normal locomotor response to casein and EAS. Heterogeneity in locomotor abnormaltiy of T and non-T cells toward casein and endotoxin-activated serum was observed in other immunodeficient patients. No direct correlation was observed between the proportion of cells in the several T cell subsets and the abnormalities of locomotion of T cells.
To determine the best predictors of chronic pulmonary disease in patients with hypogammaglobulinemia, we evaluated the clinical records, chest x-ray films, and pulmonary function tests of 10 patients with X-linked agammaglobulinemia (XLA) followed for a mean of 12.5 years, and 12 patients with common variable immunodeficiency (CVID) followed for a mean of 10.5 years. These patients, most of whom were treated with intramuscular gamma globulin and long-term oral antibiotics, had very few pneumonias after diagnosis. The patients with XLA had 0.10 pneumonias per treatment year, and the patients with CVID had 0.18 pneumonias per treatment year. Seven of the 10 patients with XLA had normal chest x-ray films 8 to 15 years after diagnosis, and none had bronchiectasis. Pulmonary disease was more common and more severe in the group with CVID, but five patients in this group also had normal chest x-ray films after long follow-up. In the entire group of 22 patients, nine of the 10 patients with abnormal chest x-ray films on most recent evaluation already had pulmonary disease at the initial visit (p = 0.00002). These studies indicate that the best predictors of good pulmonary function in patients with hypogammaglobulinemia are early diagnosis and good compliance with gamma globulin replacement therapy and oral antibiotics.
The syndrome of idiopathic CD4+ lymphocytopenia has recently been recognized and referred to as the persistent depletion of peripheral blood CD4+ T lymphocytes below 300 cells per cubic millimeter or less than 20% of total lymphocytes in the absence of either HIV infection or other known causes of immunodeficiency. The available literature indicates that neither human retroviruses (HIV-1, HIV-2, HTLV-I, HTLV-II) nor other transmissible agents play any clear-cut role in the pathogenesis. Furthermore, the epidemiologic, immunologic and clinical features of this syndrome differ substantially from those of HIV infection. The heterogeneity of both immunologic abnormalities, in addition to CD4+ depletion, and clinical course in patients with this disorder points out no common cause although in at least a subset of patients the pathogenetic pathways could be shared with common variable immunodeficiency.
Among 313 patients with serum IgG deficiency, selective IgG3 deficiency was found in 59.5%, combined IgG3 deficiency together with IgG1 deficiency in 36% and combined IgG3-IgG2 deficiency in only 4.5%. Most of the patients with IgG3 deficiency suffered from upper respiratory tract infections, but many also from recurrent bronchitis, bronchopneumonias and asthma bronchiale. Those with combined IgG3-IgG1 deficiency often suffered from obstructive lung disease and chronic lower respiratory tract infections. Other diagnoses found in patients with IgG3 deficiency were diabetes mellitus, Henoch-Schönlein, recurrent herpes simplex infections and recurrent erysipelas. IgG3 deficiency was also found in relatives of patients with common variable immunodeficiency and IgA deficiency. In one family both parents and all four children showed IgG3 deficiency, some of them also C2 deficiency. In another family 2 siblings with diabetes mellitus showed IgG3 deficiency. In still another family the mother and her daughter both with asthma bronchiale showed IgG3 deficiency. Patients with IgG3 deficiency could respond to pneumococcal vaccine and seemed to respond to immunoglobulin substitution given every or every other week.
Epidemiological studies have shown wide geographical and racial variation in the prevalence and patterns of immunodeficiency disorders. To determine the frequency of primary immunodeficiencies (PID) in Iran, the Iranian Primary Immunodeficiency Registry (IPIDR) was organized in 1999. We extracted the patient's data, by using a uniform questionnaire from their hospital records. The diagnosis of patients was based on WHO criteria. By now, 440 patients with PID, who were observed during a period of 20 years, have been registered in our registry. Among these patients, the following frequencies were found: predominantly antibody deficiency in 45.9% of patients (n = 202), phagocytic disorders in 29.09% (n = 128), T-cell disorders in 24.31% (n = 107), and complement deficiencies in 0.68% (n = 3). Common variable immunodeficiency was the most frequent disorder (n = 98), followed by chronic granulomatous disease (n = 86), ataxia telangiectasia (n = 48), x-linked agammaglobulinemia (n = 45), selective IgA deficiency (n = 42), combined immunodeficiency (n = 15), and severe combined immunodeficiency (n = 14). This study revealed that antibody deficiencies is the most frequently diagnosed primary immunodeficiency disorder in our patients, which is similar to that observed in other registries. A comparative study shows some differences between our results and other registries.
Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.
Hyper-IgM immunodeficiency (HIM) is an immunological disorder characterized by normal or elevated serum IgM levels, and reduced serum IgG and IgA levels, due to the disruption of immunoglobulin class switching in B cells. X-linked hyper-IgM is caused by the defective expression of the CD40 ligand on activated T cells, which induces immunoglobulin class switching along with some cytokines, such as interleukin 4, by the signal transduction of CD40 in B cells. We report on a Japanese girl who initially showed low serum IgM, IgG and IgA levels like patients with common variable immunodeficiency; however, in the course of time, serum IgG levels became reduced and serum IgM levels increased, resulting in the typical immunoglobulin profile of HIM. Neutropenia, one of the features of X-linked HIM, was not observed. In spite of extremely low serum IgG levels, she did not show any predisposition to severe infection, even without gammaglobulin replacement therapy. No mutation of the CD40 ligand or CD40 was detected. Sequencing of the complementarity-determining region of immunoglobulin heavy-chain genes in peripheral B lymphocytes revealed that they were all in frame, and insertion of the N region was detected. These results indicate that the heavy-chain gene rearrangement in the patient's B cells is intact. Non-X-linked HIM has heterogeneous pathogenetic mechanisms, and some groups may show the resistance to infection at the healthy donor level. The underlying defects in non-X-linked HIM might be specifically involved in class switching.
Patients with primary immunodeficiency disorders were evaluated for three aspects of natural defense: natural killer (NK) cells which lyse HSV-infected fibroblasts [NK(HSV-FS)], NK cells which lyse K562 tumor targets [NK(K562)], and interferon-alpha generation. In addition, capacity to make interferon upon challenge with other commonly used inducers was also evaluated. Most patients with severe combined immunodeficiency disease (SCID) and deficits of both T- and B-cell function demonstrated normal NK function with one or both targets. Six of eight SCID patients generated interferon-alpha at or below the lower limit of normal while only two made clearly normal levels. Six of 10 patients with Wiskott-Aldrich syndrome (WAS) had normal NK(K562) and five of 10 generated normal levels of interferon-alpha but all had severely deficient NK(HSV-FS). Patients with Bruton's agammaglobulinemia demonstrated normal NK and interferon generation, as did patients with common variable immunodeficiency, even when subdivided into patients with T-cell proliferative deficiencies and those with only hypogammaglobulinemia. Natural defense parameters may help categorize patients with SCID and WAS and help define these heterogeneous diseases.
B- and T-cell populations in 32 patients with different forms of primary immunodeficiency disease were studied. The B-cells in peripheral blood were investigated with respect to surface immunoglobulins by means of immunofluorescence. The T-cell function was studied utilizing quantitation of proliferative response to phytochemagglutinin (PHA)(1) and delayed allergy to various antigens. In 10 patients lymph node lymphocytes were also evaluated 11 male children with infantile x-linked agammaglobulinemia were divided into two subgroups. One did not show immunoglobulin spots on peripheral blood lymphocytes at all, the other contained a very low percentage of IgM- and occasionally IgA bearing lymphocytes. Eight patients with common variable immunodeficiency had moderately decreased percentages of peripheral blood and lymph node lymphocytes with surface immunoglobulins, but these patients lacked immunoglobulin secreting cells. Four cases of isolated IgA deficiency had normal or high percentages, and two cases of ataxia-telangiectasia had high percentages of lymphocytes with IgA in so called receptor distribution in both peripheral blood and lymph nodes. In three patients with infantile combined immunodeficiency that had been corrected by marrow transplantation, the percentages of Ig-bearing lymphocytes increased to normal or high levels together with establishment of functional T-cell population and ultimate secretion of serum immunoglobulins. One case of Di George syndrome reconstituted by fetal thymus transplant showed gradual decrease of B lymphocytes in circulation parallel to restoration of T-cell population.
Leukocytes from patients with several forms of immunodeficiency characterized by apparently differing defects in B-lymphocyte maturation produced few or no plasmacytoid cells in vitro, and were capable of suppressing the generation of plasma cells in co-culture with cells of normal persons, in the presence of pokeweed mitogen. Such inhibition was commonly observed in cultures which included cells from patients with primary immunoglobulin deficiency, but was not seen to a significant degree in identical co-cultures of cells from normals. The suppression observed was not dependent upon mixed leukocyte culture reactivity. Both sheep erythrocyte-rosetting lymphocytes and adherent cells appeared to participate in these effects in some patients. In one patient with common variable immunodeficiency, but not in several others, removal of suppressing cells permitted the patient's remaining cells to differentiate into plasma cells in vitro. Because of the diverse syndromes in which suppression was observed, it is likely that, in at least some hypogammaglobulinemic patients, the suppression is secondary to the disease process rather than being the primary pathogenic mechanism.
Ecto-5'-nucleotidase (ecto-5'-NT) activity was measured in human B cells at different stages of development. Ecto-5'-NT activity of B cell preparations from fetal spleen and cord blood was 5.08 and 5.59 +/- 2.8 nmol/hr/10(6) cells, respectively; that of B cell preparations from adult peripheral blood, spleen, or lymph node was fivefold to sixfold higher (27.9 +/- 12, 29.2 and 33.8 nmol/hr/10(6) cells, respectively). The increased enzyme activity in B cell preparations from adult peripheral blood as compared with cord blood paralleled increased percentages of 5'-NT+ cells (69 +/- 12% vs 32 +/- 17%) and an average of twice as much enzyme activity per positive cell. Small, resting B cells that cannot synthesize Ig in vitro in response to pokeweed mitogen (PWM) were isolated from adult peripheral blood by mouse erythrocyte rosetting. Total ecto-5'-NT activity and the percentage of 5'-NT+ cells were equivalent in total B cells and the mouse erythrocyte rosette-positive subpopulation. Thus, ecto-5'-NT activity is acquired before B cells gain the ability to differentiate into Ig-secreting plasma cells in response to PWM. Ecto-5'-NT activity was also measured in B cell preparations from eight patients with common variable immunodeficiency. Six had reduced ecto-5'-NT activity (2.83 to 15.4 nmol/hr/10(6) cells), and two had normal activity (34.7 and 58.2 nmol/hr/10(6) cells). B cells from all six patients with low ecto-5'-NT activity failed to synthesize Ig when cultured with PWM and normal irradiated T cells. Of the two patients with normal B cell ecto-5'-NT activity, one also had B cells unresponsive to PWM, but B cells from the other patient appeared to more normal, in that they synthesized IgM and IgG when cultured with PWM plus irradiated allogeneic T cells. Thus, measurement of B cell ecto-5'-NT activity allows the subclassification of patients who have a common inability to synthesize immunoglobulin in vitro response to PWM. B cells with low ecto-5'-NT activity are presumably blocked at an earlier stage in development than B cells with normal ecto-5'-NT activity. Evaluation of ecto-5'-NT activity along with the expression of other B cell surface antigens should aid in the definition of discrete stages of B cell development.
The interaction between the CD40 ligand (gp39), expressed by activated T cells, and CD40, constitutively expressed by B cells, is critical for an effective antibody response to T cell dependent antigens. Patients with X-linked hyper IgM (HIM) syndrome fail to express a functional CD40 ligand due to a mutation within the gene for gp39. As a direct consequence, HIM patients, when immunized with T dependent antigens, produce only small amounts of IgM antibody without the development of immunologic memory, amplification and switch from IgM to IgG. Mutations affecting the gene for the HIM syndrome are localized throughout the coding region of gp39 and consist predominantly of point mutations. The resulting amino acid substitutions interfere directly with the receptor binding site or lead to stop codons or deletions secondary to splice site mutations. Expression of gp39 by activated T cells from patients with common variable immunodeficiency (CVI) is low in approximately half of the patients and is associated with depressed expression of IL-2. These findings suggest that inefficient signaling via CD40 may be responsible in part for failure of B cell differentiation in CVI.
Sera from 106 blood donors, 40 patients with primary immunodeficiencies (ID) treated with gamma-globulin, and 46 patients with selective IgA deficiency were analyzed by an enzyme-linked immunosorbent assay for anti-IgA antibodies. Increased levels of antibodies to IgA were found in 5.6% of the blood donors, 17.5% of the ID patients, and 36.8% of the isolated IgA deficiencies. The percentage was higher in patients with IgA and IgG2 deficiencies (50%). The percentage of patients having increased levels of anti-IgA antibodies was similar to the total prevalence of the 10 other autoantibodies studied. These anti-IgA antibodies were mainly of the IgG class, except from one blood donor with IgM antibodies, and two patients, one with isolated IgA deficiency and the other with common variable immunodeficiency who had anti-IgA antibodies of the IgE class. The latter patient developed a near fatal anaphylactic reaction when intravenous gamma-globulin was administered. Most of the patients with severe adverse reactions to gamma-globulin did not present anti-IgA antibodies. Our data suggest that at least in some immunodeficient patients the elevated amounts of anti-IgA antibodies are not related to the administration of exogenous IgA. The importance of measuring anti-IgA antibodies of the IgG and IgE isotypes in IgA-deficient patients as well as in patients in treatment with gamma-globulin is emphasized.
Peripheral blood lymphocytes (PBL) from patients with various forms of primary and secondary immunodeficiencies and from 30 healthy control persons were examined for their capacity to show terminal B-cell maturation and immunoglobulin (Ig) synthesis in vitro following pokeweed mitogen (PWM) stimulation. PBL were cultured for 9 days with or without PWM and the percentages of B-cells or plasma cells with strongly positive cytoplasmic Ig (CIg+) were determined by indirect immunofluorescence on methanol fixed cytocentrifuged lymphocyte smears. In addition, newly synthesized IgA, IgG and IgM was measured in the cell free culture supernatant by means of a sensitive microplate ELISA. In 29 out of 30 control cultures the proportion of CIg+-cells increased markedly following 9-day stimulation with PWM. CIg+-cells and newly synthesized Ig were significantly correlated. In a group of 18 patients with common variable immunodeficiency (CVID) maturation to CIg+-cells was greatly impaired and the in vitro production of IgA and IgG was reduced. Two infants with severe combined immunodeficiency (SCID) failed to produce Ig prior to and following haplo-identical bone marrow transplantation despite the presence of immature B-cells. A heterogeneous group of secondary immunodeficiencies showed different forms of an impaired terminal B-cell maturation and a reduced capacity to synthesize Ig in vitro. The described PWM culture techniques in combination with the evaluation of CIg+-cells and the measurement of newly synthesized Ig in the culture supernatant proved to be a reliable in vitro correlate for terminal B-cell maturation and represent an important tool for the classification of humoral immunodeficiencies.
Previous reports of an association between constitutional chromosome 18 abnormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable immunodeficiency (CVID), characterized by a lack of additional isotypes. Our previous linkage analysis of 83 multiple-case IgAD/CVID families containing 449 informative pedigree members showed a significantly increased allele sharing in the chromosome region 6p21 consistent with allelic associations in family-based and case-control studies and provided the evidence for a predisposing locus, termed IGAD1, in the proximal part of the MHC. We have typed the same family material at 17 chromosome 18 marker loci with the average intermarker distance of 7 cM. A total of 7633 genotypes were analyzed in a nonparametric linkage analysis, but none of the marker loci exhibited a significantly increased allele sharing in affected family members. In addition, reverse painting and deletion mapping of a panel of constitutional chromosome 18 deletions/translocations showed the presence of IgA-deficient and IgA-proficient patients with the same abnormality and did not reveal a region commonly deleted. The linkage analysis of chromosome 8 and 21 regions involved in reciprocal translocations t(8;18) and t(18;21), which were identified in two patients lacking IgA, did not disclose a significant allele sharing. Although these results do not exclude the presence of a minor predisposing locus on this chromosome, such a putative locus would confer a population risk of developing IgAD/CVID much lower than IGAD1.