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MST1 deficiency causes T and B cell lymphopenia, resulting in combined immunodeficiency. However, MST1-deficient patients also exhibit autoimmune-like symptoms such as hypergammaglobulinemia and autoantibody production. Recent studies have shown that the autoimmune responses observed in MST1-deficient patients were most likely attributable to defective regulatory T (Treg) cells instead of intrinsic signals in MST1-lacking B cells. Nevertheless, it is not determined how MST1 deficiency in T cells breaks B cell tolerance and causes systemic autoimmune-like phenotypes. In this study, we confirmed that Mst1 -/- mice developed hypergammaglobulinemia associated with increased levels of IgG, IgA, and IgE. We also showed that uncontrolled B cell responses were resulted from the IL-4-rich environment created by CD4 + T cells. Defective MST1-FOXO1 signaling down-regulated Treg cells, resulting in the collapse of immune tolerance where the populations of Th2 and T follicular helper cells expanded. In conclusion, we suggest that MST1 acts as a molecular brake to maintain immune tolerance by regulating T cell-mediated B cell activation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hyper-IgG4 syndrome, or IgG4-related systemic disease (IgG4-RSD), has been recently characterized by the association of a focal or diffuse enlargement in one or more organs, elevated levels of serum IgG4 and histopathological findings including "storiform" fibrosis and prominent infiltration of lymphocytes and IgG4-positive plasma cells. Pancreas was the first organ involved with sclerosing pancreatitis (or autoimmune pancreatitis). Since this first description, many extrapancreatic lesions have been described, even in the absence of pancreatitis and include sialadenitis, lacrimal gland inflammation, lymphadenopathy, aortitis, sclerosing cholangitis, tubulointerstitial nephritis, retroperitoneal fibrosis or inflammatory pseudotumors. Multiorgan lesions can occur synchronously or metachronously in a same patient, usually after 50 years of age. They all share common histopathological findings. The disease often responds well to corticosteroid therapy. In this literature review on IgG4-RSD, we present historical, epidemiological and clinical characteristics, and we review the biological and histological diagnostic criteria. To date there is no international validated diagnostic criteria. Pathophysiological hypothesis and therapeutic approaches are also discussed., (Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Manifestations of chronic graft-versus-host disease (cGVHD) can resemble those seen in immunodeficiency states and autoimmune disorders. Reports by us and others suggest an involvement of B cells in the pathogenesis of cGVHD. We investigated B-lymphocyte subpopulations in cGVHD cohorts defined by serum immunoglobulin G (IgG) levels to characterize novel biomarkers for impairment of humoral immunity after allogeneic hematopoietic stem cell transplantation. Seventy-six patients were enrolled a median of 46 months after hematopoietic stem cell transplantation. The hypogammaglobulinemia group had significantly diminished CD19(+) B cells (165 vs 454 vs 417 × 10⁶L) with elevated CD19(+)CD21(low) immature (16.5%, 7.7%, and 9.1%) and CD19(+)CD21(int-high)CD38(high)IgM(high) transitional (10.5% vs 4.2% vs 6.3%) B-cell proportions compared with the normogammaglobulinemia and hypergammaglobulinemia groups. CD19(+)CD10(-)CD27(-)CD21(high) naive B cells were highly elevated in all patients with cGVHD. CD19(+)CD27(+)IgD(+) non-class-switched (4 vs 12 vs 11 × 10⁶/L) and class-switched (7 vs 35 vs 42 × 10⁶/L) memory B cells were significantly lower in the hypogammaglobulinemia group compared with the others. Besides significantly higher B-cell activation factor/B-cell ratios, significantly more cGVHD patients with hypergammaglobulinemia had autoantibodies compared with the hypogammaglobulinemia subgroup (68% vs 24%, P = .024). In conclusion, B-cell subpopulations can serve as novel cellular biomarkers for immunodeficiency and autoimmunity indicating different pathogenetic mechanisms of cGVHD and encouraging future prospective longitudinal studies.

Objectives: Hypergammaglobulinemia is one of the manifestations of B-cell dysfunction associated with untreated HIV infection. Globulin levels are not routinely measured in HIV-infected patients on treatment. The purpose of this study was to evaluate the effect of highly active antiretroviral therapy (HAART) on calculated globulin levels., Methods: The study group consisted of 75 HIV-infected treatment-naïve patients, starting HAART, and virologically suppressed for ≥6 months; 16 patients (21%) were HIV-HCV-co-infected., Results: All patients experienced significant increases in CD4 cell counts at 6 and 12 months after HAART initiation compared to baseline (p<0.01 for all comparisons). The increase in CD4 cell counts was significant regardless of the HCV infection status. Significant increases in albumin levels (p<0.05 at 6 and 12 months), reductions in total protein (p<0.01 at 1 year; not significant at 6 months), and concomitant significant reductions in the calculated globulin levels (p<0.001 at 6 and 12 months) after HAART initiation compared to baseline were observed for the whole group. However, less than half the patients achieved a normal albumin/globulin ratio at 1 year. HIV-monoinfected patients had significant changes in albumin, total protein, and calculated globulin levels. In contrast, HIV-HCV-co-infected patients only showed significant increases in albumin levels., Conclusions: Future studies to evaluate the potential use of calculated globulin levels and albumin/globulin ratios as readily available surrogate markers of B-cell immune reconstitution in HIV-monoinfected patients are warranted., (Published by Elsevier Ltd.)

Purpose: Autoimmune manifestations (AIM) are associated to common variable immunodeficiency (CVI) in about 20 to 25% of the cases. This study presents the clinical, biological characteristics and the evolution of nine patients developing CVI and AIM. A peripheral B-cell compartment analysis has been performed in seven cases., Method: This multicenter retrospective study analyses nine patients, six men and three women, within a population of 32 CVI., Results: The mean age was 27 years at the time of diagnosis of AIM and 30 years at the time of diagnosis of CVI. The diagnosis of AIM preceded the diagnosis of CVI in five cases. Thirteen AIM of different types were observed: autoimmune hemolytic anemia (AHA, 3), immune thrombocytopenic purpura (ITP, 2), Evan's syndrome (2), primary biliary cirrhosis (1), rheumatoid arthritis (1), alopecia totalis (1), myasthenia gravis (1). The peripheral B-cell compartment was investigated in seven patients: five patients with autoimmune cytopenia presented with a diminution of memory B cells (CD27+IgD-) and immature B cells (CD21-) levels; the patient with primary biliary cirrhosis and myasthenia gravis had only a diminution of memory B cells level; the last patient with ITP presented with a normal level of memory B cells. Five among the seven patients with autoimmune cytopenia required a specific treatment using corticosteroids, high dosages of intravenous immunoglobulin, then splenectomy after failure of the medical management, with severe infectious complications in one case., Conclusion: The association of AIM and CVI is not fortuitous. The most common AIM is autoimmune cytopenia. The peripheral B-cell compartment analyses show that a majority of patients have a defect in memory B-cells. Treatment regimens are not standardized and splenectomy increases the risk of infectious complications.

Hypergammaglobulinemia and defective humoral immunity are hallmarks of HIV-1 infection. Naive B cells have been recently suggested as the major source of hypergammaglobulinemia in chronic viral infections. We recently reported that HIV-1-infected patients carry low levels of memory B cells. Here we studied whether defects in the naive and memory B cells in HIV-1-infected patients translated into hypergammaglobulinemia and defective humoral immunity against specific antigens. Naive B cells from HIV-1-infected patients exhibited abnormal expression of the activation/differentiation markers CD70 and leukocyte-associated Ig-like receptor (LAIR-1). Activated naive B cells from patients showed a significant increase in the intracellular immunoglobulin G (IgG) content ex vivo and this activated phenotype correlated to hypergammaglobulinemia and to the ability of naive B cells from patients to secrete IgG in vitro. We analyzed the levels of antibodies to tetanus toxoid, measles, and HIV-1 in relation to memory B cells and observed a significant reduction of antigen-specific antibodies in patients with low-memory B lymphocytes. Nevertheless, hypergammaglobulinemia and levels of polyspecific self-reactive antibodies were comparable in patients with normal and low memory B cells. We conclude that reduction of memory B lymphocytes in HIV-1 infection correlates with defective humoral immunity and that hyperactivated naive B cells may represent the source of abnormal IgG production in HIV-1 infection. Our results may be relevant to the design of HIV-1 therapeutical vaccines and to the clinical management of HIV-1-infected patients.

CD40 ligand (CD40L) deficiency causes recurrent sinopulmonary infection, Pneumocystis carinii pneumonia, and Cryptosporidium parvum infection. Approximately 40% to 50% of patients survive to the third decade: long-term survival is unclear. Hematopoietic stem cell transplantation (HSCT) is curative. We present a retrospective analysis of 38 European patients undergoing HSCT for CD40L deficiency in 8 European countries between 1993 and 2002. Donor stem cell source included 14 HLA-identical siblings, 22 unrelated donors, and 2 phenotypically matched parental stem cells (12 T-cell depleted). Of the patients, 34 engrafted and 26 (68%) survived; 3 had autologous reconstitution, 22 (58%) were cured, and 1 engrafted but has poor T-cell immune reconstitution. There were 18 evaluated patients who responded to vaccination. Of the patients, 12 (32%) died from infection-related complications, with severe cryptosporidiosis in 6. Grades 2 to 4 graft-versus-host disease (GvHD) associated with infection occurred in 6 of 12 fatal cases. HSCT cured 58% of patients, 72% of those without hepatic disease. Early T-cell function following whole marrow HSCT may limit cryptosporidial disease, but survival was similar after T-cell-depleted HSCT. Preexisting lung damage was the most important adverse risk factor. Further studies will determine optimal timing and type of HSCT.

Immunodeficiency and autoimmune phenomena may occur concomitantly in the same individual. Many immune deficiency syndromes, mainly humoral defects, are associated with autoimmune disorders. Hematological manifestations, such as thrombocytopenia and hemolytic anemia, are the most common presentation, but many other autoimmune mediated conditions have also been described. Persistent antigen stimulation, due to an inherently defective immune system ability to eradicate pathogenesis is the primary cause leading to autoimmunity in patients with primary immunodeficiency states. Other factors leading to the increase incidence of autoimmune manifestion will be discussed in the present review. Treatment with intravenous gammagluobuilin may ameliorate the autoimmune disorder and bone marrow transplantation can cure both conditions.

Cadmium is a pervasive environmental contaminant. The primary route of exposure to the general population occurs via contaminated drinking water or food supplies. Our hypothesis was that cadmium could be a trigger for inducing autoimmune disease (AD) in genetically predisposed populations. Therefore, New Zealand Black/White F1 (NZBW) mice were exposed to cadmium via drinking water. Mice were exposed to: 0, 3, 30, 3000 or 10000 parts per billion (ppb) of cadmium in tap water for 2, 4, 28, or 31 weeks. After 4 weeks of exposure, in the group of mice exposed to 10000 ppb cadmium, there was an increased incidence of antinuclear antibodies (ANA). There was also deposition of immune complexes in all groups after 4 weeks of exposure. After 31 weeks, there were increases in IgG2a in mice exposed to low doses of cadmium. In an attempt to establish the progression from an autoimmune reaction to the development of AD, the biological marker for AD, proteinuria, was assessed. Onset of proteinuria was exacerbated by 11 weeks in mice exposed to cadmium. This data suggests that short-term exposure may result in a type of autoimmune reaction since the mice are beginning to produce ANA after only 4 weeks of exposure and there is immune-complex deposition in the kidney. Long-term exposure to cadmium appears to result in the exacerbation of AD as indicated by the development of proteinuria and continued presence of immune complexes in the kidney. The mechanism may involve the increased production of IgG2a, which is capable of forming immune complexes and causing autoimmune glomerulonephritis.

Hereditary periodic fever syndromes are defined as recurrent attacks of generalized inflammation for which no infectious or auto-immune cause can be identified. Minimal clinical variations, a unique biochemical-specific abnormality and the mode of genetic inheritance distinguish the four main diseases: familial Mediterranean fever, hyper-immunoglobulinemia D, TNF-receptor-associated periodic syndrome (TRAPS) and Muckle Wells syndrome. It presents with prolonged attacks of fever and severe localized inflammation. TRAPS is caused by dominantly inherited mutations in the gene encoding the first TNF receptor, which result in decreased serum levels of soluble TNF-receptor leading to inflammation due to unopposed TNF-alpha action. Corticosteroid treatment is not completely effective in most TRAPS patients. Preliminary experiences with recombinant TNF-receptor analogues in the treatment appear be promising.

NZB mice spontaneously develop an autoimmune disease characterized by autoimmune hemolytic anemia, thymic atrophy, lymphoid hyperplasia, and hypergammaglobulinemia. The aim of this study was to examine the hypothesis that cryoglobulins may have an immunoregulatory effect on the autoimmune process. The effect of human monoclonal IgM cryoglobulin preparations (including Cryo13, Cryo14, and Cryo16) isolated from the serum of patients with Waldenström's macroglobulinemia on the autoimmune disease of NZB mice was therefore studied. The effect of cryoglobulin preparations was evaluated on several disease parameters, i.e., survival, severity of anemia, and serum IgM and IgG levels (hypergammaglobulinemia). We found that immunization of NZB mice with Cryo13 at 3 months of age delayed the course of the disease, whereas Cryo14 and Cryo16 were ineffective. Furthermore, the effect of Cryo13 was long lasting. On the other hand, Cryo13 was able to react with 8 of 32 mouse monoclonal natural IgM autoantibodies. In contrast, Cryo14 was able to bind only 2 and Cryo16 none of these mouse monoclonal IgM antibodies. These results indicate that, in this model of autoimmune pathology, the beneficial effect of Cryo13 is mediated by its idiotypic interaction with the murine natural autoantibody network., (Copyright 2000 Academic Press.)

Introduction: Hyper-reactive malarial splenomegaly (HMS) syndrome related to abnormal immunologic response to repeated malarial infections is unusual in European expatriates., Exegesis: We report the case of a 72-year-old white male patient who had been residing in the Congo and developed a typical clinical features of hyperactive malarial syndrome characterized by massive splenomegaly with hypersplenism, high titers of malarial IgM antibodies, IgM macroglobulinemia, liver and medullary lymphocytic proliferation, and a clinical and immunological response to long-term chloroquine therapy., Conclusion: Criteria for the diagnosis of hyper-reactive malarial splenomegaly are useful. However, making a distinction from malignant lymphoproliferative disorders is difficult, as a sustained response to chloroquine is required. Therefore, chloroquine appears to have a regulatory effect on the immune system.

Middle-aged patients who initially present with a progressive cerebellar ataxia, in the absence of a known familial pattern are often referred to under the descriptive diagnosis of 'idiopathic' late onset cerebellar ataxia. If these patients in time develop additional pyramidal or extrapyramidal features then they should be labeled as olivopontocerebellar atrophy (sOPCA). This case report describes a patient with OPCA with cerebellar ataxia as the presenting and most prominent feature in combination with dementia, pyramidal signs, cortical cataract of the posterior pole and a raised IgG index in cerebrospinal fluid. To the best of our knowledge this combination of signs and symptoms have not been described before.

Cardiomyopathy due to monoclonal light chain deposits is a complication of plasma cell disorders. The deposits may be either fibrillar as in light chain amyloid or nonfibrillar as in light chain deposition disease. The reasons for these structural differences are still unknown. We characterized the myocardial deposits by immunohistochemical examination of sections and extraction and biochemical analysis of the tissue deposits in a patient (MCM) who died of myeloma and systemic light chain deposition disease. Amino acid sequence analysis of the extracted nonfibrillar MCM kappa-light chain reveals that it belongs to the L12a germline subset of the kappa(I) protein and contains five distinctive amino acid substitutions (three in the framework region III and two in the complementarity-determining region III) that have not been reported previously in the same positions in other kappa(I) light chains. The theoretically determined isoelectric point (pI 8.21) of the MCM light chain is high compared with the low isoelectric point of other Bence Jones proteins from subjects without light chain deposition disease. The diffuse binding to basement membranes and the high isoelectric point of the MCM kappa-light chain suggest electrostatic interaction as a possible mechanism of tissue deposition. The spatial locations of the five distinctive residues and a sixth rare substitution of the MCM protein modeled on the backbone structure of REI, a kappa(I)-soluble Bence Jones light chain of known three-dimensional structure, may be responsible for protein destabilization, partial unfolding, and aggregation leading to tissue deposition.

A 7-year-old patient is reported who suffered from fatigue and jaundice due to chronic hepatitis. He had acquired hepatitis A virus infection in his community and communicated the disease to his German family 4 weeks later. While the other family members recovered from acute viral hepatitis A, the patient presented 10 weeks after the onset of hyperbilirubinemia (12 mg/dl) with the histology of chronic hepatitis, absence of markers for viral persistence, presence of autoantibodies against smooth muscle (1:320) and the asialoglycoprotein receptor (1:600), and marked hypergammaglobulinemia (3700 mg/dl), leading to the diagnosis of autoimmune hepatitis. The patient received immunosuppressive therapy, symptoms of liver disease disappeared, and autoantibodies cleared from circulation. The case is discussed in the context of a putative virus-induced autoimmune hepatitis in childhood. Autoimmune hepatitis may be induced by an external trigger. Hepatitis A virus infection is one of probably several triggers that may induce autoimmune hepatitis in predisposed individuals.

The diffuse dermal immunofluorescence (DDIF) observed in human skin biopsies that is produced by fluorochrome-conjugated antisera reactive with human immunoglobulin G (IgG) has commonly been viewed in the past as an artifact of direct immunofluorescence microscopy. However, it has been our belief that DDIF, which has been observed in 14% of the biopsies processed in our laboratory, might represent an in vivo phenomenon of excess unbound dermal interstitial immunoglobulin G reflective of elevated serum IgG levels. To examine this hypothesis, we carried out a blinded prospective study of the frequency of DDIF in two groups of age- and sex-matched patients that differed with respect to the presence or absence of serum hypergammaglobulinemia (gamma globulin greater than 2.5 mg/100 ml). The subjective intensity of DDIF and the fluorescein-isothiocyanate (FITC) conjugated anti-human IgG antibody titer at which point DDIF disappeared were both compared with serum gamma globulin levels. Also, the amount of IgG that could be extracted from biopsy specimens by an overnight phosphate-buffered saline (PBS) elution procedure was quantified by solid-phase immunoassay. We noted a trend of increased DDIF intensity with increasing serum gamma globulin levels. In addition, there was a relatively weak but significant positive correlation between DDIF endpoint titers and serum gamma globulin levels (p = 0.05, r = 0.429). The strongest positive statistical correlation observed in the study was between the quantities of IgG that could be eluted from skin biopsies and serum gamma globulin levels (p = 0.01, r = 0.599). These findings suggest that DDIF is a true biologic phenomenon reflective of elevated serum gamma globulin levels and demonstrate that simple overnight elution of unbound dermal IgG can unmask the presence of disease-related, specifically-bound IgG.

The two sulfated glucuronic acid containing glycolipids, sulfate-3-glucuronyl paragloboside (SGPG) and sulfate-3-glucuronyl lactosaminyl paragloboside (SGLPG), were prepared by ion exchange chromatography of lipid extracts from bovine cauda equina. Thin layer chromatography (TLC) immunostaining and an enzyme-linked immunosorbent assay (ELISA) were used to show that the SGPG/SGLPG fraction was free of crossreactive antigenic components such as gangliosides. The results obtained by ELISA demonstrate that sera of all patients were validated IgM monoclonal anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy display high titer antibodies with high affinity type titration curves. These antibodies were absent from the sera of 16 patients with other neurological diseases and ten normal controls. ELISA with SGPG/SGLPG as an antigen appears to be a valuable and highly specific immunodiagnostic test for determining anti-MAG antibody titers in the sera of patients. The amount (approximately 0.4 mg) of SGPG/SGLPG partially purified from 10 g of fresh tissue is sufficient for the preparation of approximately 100 96-well plates for ELISA procedures.

The interest of new methodologies (electrophoresis in agarose, immunofixation, quantitation of Ig G, Ig A, Ig M and light chains kappa/lambda ratio) to diagnose monoclonal gammopathies, was discussed. A strategy using a combination of these new procedures was exposed. Serum level of bêta-2 microglobulin can be used to monitor response to therapy in myeloma when the quantitation of monoclonal Ig is not possible.

We have developed an immunoradiometric assay for IgE antibodies to Staphylococcus aureus (Staph IgE-Ab) which uses purified cell walls (PCW) from the Wood 46 strain of S. aureus as an immunosorbent. We compared Wood 46 PCW and whole organisms (WO) as immunosorbents for Staph IgE-Ab by performing tests on sera from patients with atopic dermatitis (AD) or the hyperimmunoglobulin E syndrome (hyper IgE syndrome). Sera with Staph IgE-Ab demonstrated dose-dependent binding to PCW and WO, but the ratio of specific to non-specific binding was much greater with PCW. Mean non-specific binding to WO was greater than to PCW, 5% versus 2%; and non-specific binding to WO varied directly with the serum concentration of IgE. Results of tests on patients' sera indicated that PCW are required in screening assays for Staph IgE-Ab to avoid false positive results caused by high levels of non-specific binding to WO.

A 5-year-old girl had a chronic disease characterised by fever, lymphoid hyperplasia, interstitial pneumonitis, thrombocytopenia, and polyclonal hypergammaglobulinaemia. Evidence for severe, persistent Epstein-Barr virus (E.B.V.) infection was found: titres of antibody to E.B.V. viral capsid antigen (IgM and IgG) and early antigen were extremely high, cells containing E.B.V.-associated nuclear antigen (E.B.N.A.) were found in lymph nodes and blood, and spontaneous permanent lymphoblastoid cell lines were established from both sources over a period of a year. After exacerbation of the polyclonal proliferation of immunoblasts the patient died 19 months after the onset of the disease. No defect in humoral or cellular immunity was detected, except for a selective defect in immune interferon secretion by peripheral mononuclear cells. Our results suggest an important role for immune interferon in host defence against E.B.V. infection and in the regulation of immune responses.

Three patients presented with gradual onset of proximal muscle weakness. Electromyography and muscle biopsy were abnormal in each patient and typical of myositis. All three had an IgG kappa monoclonal paraprotein in the serum. Examination of muscle biopsy specimens by direct immunofluorescence revealed linear deposits of IgG kappa along the sarcolemmal basement membrane of individual fibres. Stains for lambda light chains, other immunoglobulins, and complement components were negative. Plasmapheresis and immunosuppressive drugs produced clinical improvement in all three patients. Muscle biopsies were taken from two of the patients after plasma exchange and drug therapy and showed no immune deposits. These observations suggest a possible cause-and-effect relation between the serum paraprotein and the inflammatory myopathy in these patients.

In addition to the well-known T-cell dysfunctions in AIDS, hypergammaglobulinemia, mostly IgG, and autoimmune phenomena indicate that B cells are also involved. Reports of HIV-infected and activated B cells suggest T cell-independent B-cell abnormalities. In order to assess the IgG subclasses involved in hypergammaglobulinemia, we examined all four IgG subclasses in sera and in vitro with an enzyme-linked immunosorbent assay (ELISA). The in vitro studies included 7-day cultures of mononuclear cells and highly purified B cells stimulated with a T cell-independent polyclonal B-cell activator (Klebsiella pneumoniae, KlebsM). Cultures were done with cells from seven patients with AIDS, seven patients with persistent generalized lymph node enlargement and HIV antibodies, and normal controls. In vivo, hypergammaglobulinemia was found to be restricted to the IgG1 subclass. In vitro, high spontaneous levels of IgG were not elevated significantly under stimulatory conditions, as demonstrated by the measurement of all four IgG subclasses in the culture supernatants. In vitro, hypergammaglobulinemia also resulted from IgG1. These results indicate that there are B-cell abnormalities in pre-AIDS and AIDS, in that the B-cell preactivation in vivo resulting in hypergammaglobulinemia is restricted to IgG1.

Hyperimmunoglobulinemia E is characterized by recurrent bacterial sinopulmonary and skin infections from birth or early childhood, with IgE levels at least 10 times greater than the upper limits of normal. The following case describes a young black woman with hyperimmunoglobulinemia E syndrome who had an uneventful pregnancy and delivery. The infant has been diagnosed as suffering from hyperimmunoglobulinemia E syndrome as well.

We studied the anti-IgG-induced agglutination of both normal and abnormal red blood cells (RBC) using a sensitive, automated antiglobulin test. Normal RBC agglutinated strongly with anti-IgG antibody, indicating that IgG was present on the erythrocyte membrane. Young RBC, recovered by centrifugation from a normal RBC population, agglutinated with anti-IgG less than the old cells, suggesting that immunoglobulin G accumulated gradually on the RBC membrane in vivo. The degree of anti-IgG-induced RBC agglutination correlated negatively with the reticulocyte count and positively with the concentration of plasma IgG. RBC from patients with hypogammaglobulinemia appeared to have a low subnormal quantity of membrane-bound IgG, whereas the reverse was the case in hypergammaglobulinemia. During hemolytic episodes, RBC of patients with hereditary spherocytosis agglutinated poorly with anti-IgG, apparently due to predominance of young RBC. RBC of patients with nonspherocytic. Coombs-negative, nonimmune hemolytic anemia usually also agglutinated poorly with anti-IgG. However, in some cases of active hemolytic anemia, decreased agglutination with anti-IgG was not observed, suggesting that these young RBC had increased amounts of membrane-bound IgG.

One hundred seventy-five patients with a serum monoclonal IgG who had been followed up for more than 5 years without the development of multiple myeloma, amyloidosis, or other serious diseases were designated as having MGUS. The monoclonal IgG of 83% of patients was classified as IgG1; that of 9%, IgG2; that of 6%, IgG3; and that of 2%, IgG4. The median values for hemoglobin, leukocytes, platelets, calcium, creatinine, size of the M spike, and plasma cell content in the bone marrow were not significantly different in the four subclass groups. The IgA level was reduced in 8% and the IgM in 20% of the total group. The uninvolved IgG subclass levels were reduced in 81% of the IgG1 patients and in all the IgG2, IgG3, and IgG4 patients. The patients with MGUS wer compared to 229 patients with multiple myeloma. The monoclonal IgG of the myeloma patients was classified as IgG1 (73%), IgG2 (14%), IgG3 (8%), and IgG4 (6%). The median hemoglobin values were higher in IgG3 and IgG4 groups. Renal insufficiency and size of the M protein spike were similar in the four subclass groups. Either IgA or IgM was reduced in 75% of the patients. The uninvolved IgG subclasses were reduced in 96.5% of all patients. The 5-year actuarial survival was 30% for the IgG1 group and 33% for the IgG2 group. Twenty patients with MGUS subsequently developed multiple myeloma. Analysis of the results from these patients did not show a difference from the other MGUS patients. The results suggest that the IgG subclass in MGUS does not affect either the features of the disease or the tendency for later development of multiple myeloma.

The relationship between serum and CSF IgG has been analysed: (1) In patients with a normal CSF concentration of albumin, no correlation can be demonstrated between serum IgG and CSF IgG. (2) In cases where the CSF albumin concentration is elevated (i.e. transudation), local synthesis of IgG can be determined by reference of the degree of transudation of albumin and the serum IgG concentration. The combination of local IgG synthesis and transudation (meningitic pattern) is common. Most pure transudates are of "non-inflammatory" type. A very simple formula is proposed which evaluates the relationship between local and general immunity in all neurological diseases.

Hypergammaglobulinemia, chronic endobronchial infection with Pseudomonas aeruginosa (PA), and the resulting systemic humoral immune response to PA are each associated with worsened clinical status and prognosis in patients with cystic fibrosis (CF). Major serum immunoglobulin isotype levels (IgG, IgA, IgM, and IgG1-4 subclasses) were measured in 31 CF patients and ten control subjects. Immunoglobulin levels were related to airway infection with PA and the resulting IgG antibody response against PA lipopolysaccharide (LPS). Hyperimmunoglobulinemia G was present with elevated IgG1 and IgG2 in 48 percent, IgG3 in 52 percent, and IgG4 in 42 percent of CF patients. The PA infection was associated with striking increases in IgG2. IgG2 levels correlated well with IgG2 antibodies to PA LPS (r = +0.70, p less than 0.001). However, even CF patients who were not infected with PA had an increased prevalence of high IgG3 (p less than 0.05) and IgG4 (p less than 0.01). The PA infection thus appears to be a major, but not the only factor causing hypergammaglobulinemia in CF.

Hyper-IgE syndrome (HIE) appears to be related to an immunoregulatory imbalance characterized by severe deficiency of suppressor T cells, elevated levels of IgE antibodies, and repeated infection of various organ systems. We report the association of HIE syndrome in two definite cases and one probable case of vernal conjunctivitis. This association suggests that T cell-mediated imbalance may be one factor in the pathogenesis of vernal conjunctivitis.

Recently the rather frequent occurrence of benign monoclonal gammopathy (BMG) has been reported in peripheral neuropathy. Sometimes this syndrome is part of a multisystemic disorder in which organomegaly, endocrine disturbances, skin changes and focal bone lesions may also occur. The clinical picture and the cerebro-spinal fluid findings resemble the chronic relapsing Guillain-Barré syndrome. The polyneuropathy seems to be of the primarily demyelinating type. The pathogenetic relationship with the gammopathy is as yet not clear, but treatment of the plasma cell dyscrasia has a favourable effect on the polyneuropathy. We report our experiences with 5 patients with polyneuropathy and BMG and compare our clinical, laboratory and histological data with the literature.

In 38 asthmatic patients (34 children and 4 adults) raised serum concentrations of IgE and the IgG4 subclass were found to correlate with the clinical picture. 5 children with eczema, asthma, and hayfever had grossly increased concentrations of both immunoglobulins, as did 4 adults who had had atopic eczema as children. Raised concentrations of just one of the immunoglobulin classes (i.e., IgE or IgG4) did not seem to be associated with atopic eczema. 75% of the asthmatic children in whom serum-IgG4 was raised had not shown a satisfactory response to disodium cromoglycate and required steroids to control their asthma; but 82% of patients in whom only IgE was raised responded satisfactorily to disodium cromoglycate.

A therapeutic immunoadsorption system was developed that can remove IgE effectively and specifically from the plasma of patients with an allergy or other hyper-IgE syndrome. The immunoadsorbent (IA) consists of immunoaffinity purified anti-IgE antibody (a-IgE ab) immobilized on controlled pore glass beads (50 nm pore size). Adsorption isotherms for IgE, which were reduced by the Freundlich adsorption equation, were obtained with IA that immobilized various amounts of a-IgE ab. An optimum amount of a-IgE ab to be immobilized was selected. IA worked sufficiently in a wide range of IgE concentrations. Clinical treatment requires an amount of 41 mg of IgE to be removed from a patient's plasma for 3 h. An IA for clinical use was designed to contain 10 g of the support binding 325 mg or more of the antibody. In fact, our study in vitro simulating a clinical case showed that serum IgE was removed by IA, as expected: the level decreased from 11,000 to 3000 U/ml after a 3 h perfusion (1 U = 2.3 ng). A very small amount of a-IgE ab (goat IgG) was found to be detached from IA by flowing plasma; the average level was 20 ng/ml, which seems to be safe. However, we installed the second column in a circuit that adsorbs a-IgE ab leaked into plasma, because the amounts of a-IgE ab infused into the patient must be minimized. The second column contained IgE immobilized on the same support, since IgE as a ligand adsorbed more a-IgE ab than did anti-goat IgG antibody. This is an effective and safe therapeutic immunoadsorption system and has been subjected to clinical tests.

The presence of an IgG oligoclonal pattern was investigated by isoelectric focusing and immuno detection in 151 individuals over 60 years of age. One hundred are individuals with no detectable monoclonal anomaly and among them, 22 exhibit an oligoclonal pattern. The others are 27 patients with a benign and 24 with a malign monoclonal dysglobulinemia, including respectively 9 and 2 oligoclonal patterns. In all groups the oligoclonal pattern is always found among the oldest individuals. The small association found between this special distribution of the IgG and the benign monoclonal dysglobulinemia seems to be most probably in favour of aging. The IgG oligoclonal distribution associated to a monoclonal component would not be a discriminating argument for malignant or benign monoclonal proliferation diagnosis.

Although multiple myeloma is a disease of plasma cells, abnormalities have been detected in both B and T lymphocytes in peripheral blood. Although multiple myeloma patients are deficient in surface Ig (sIg)-positive B lymphocytes, analysis of lymphocytes present in blood indicates an abnormally large pool of circulating pre-B cells. These pre-B cells express BA-1, do not bear sIg, and contain cytoplasmic mu chains. High numbers of pre-B cells occur in 88% of individuals with frank myeloma and in 44% of individuals with monoclonal gammopathy of undetermined significance. Pre-B cells bearing BA-1 differ between patients in their expression of HLA-DR and receptors for peanut agglutinin (PNA). Those pre-B cells in myeloma patients are either BA-1+ PNA- HLA-DR+ (54% of patients) or BA-1+ PNA+ HLA-DR- (30% of patients), or have a mixture of phenotypes (14% of patients). Pre-B cells of the PNA- phenotype are almost always HLA-DR+, and PNA+ pre-B cells are HLA-DR-. Within the same patient, the pre-B cell population varies by both quantitative and qualitative definitions. The number of pre-B cells may increase 460-fold and temporal shifts of surface phenotype from BA-1+ PNA- to BA-1+ PNA+ or vice versa have been detected. These observations indicate an abnormality in the B lymphocyte differentiation pathway leading to pre-B cells in the periphery that vary in number and cell surface phenotype, and that are unable to express sIg.

Invented 20 years age, crossed immunoelectrophoresis (X-IEP) today is a technique of unusual power and myriad application. It combines very high resolution with exquisite specificity by alloying 2-dimensional electrophoresis with immunoprecipitation for symbiotic new potentialities. The consequent matchless quantitative/qualitative capabilities of X-IEP for analyzing antigens in complex mixtures, particularly by their idiomatic internal comparison, are still not widely recognized. Because of this and the supposed complications of its use and interpretation, X-IEP is more rarely used than it should be. This essay discusses contemporary X-IEP with the particular aims of demonstrating that it is not difficult to use and of explaining with selected examples why it is peculiarly powerful for analyzing antigen mixtures like the body fluids, tissue and cell extracts, and microbial homogenates.

A method is described for preparative isoelectric focusing in agarose using low electroendosmotic agarose. Resolution comparable to that seen on analytical polyacrylamide gels is attainable as demonstrated by the isolation of bands with identical idiotypes from the serum of a patient with a monoclonal gammopathy.