Immunoglobulin G subclasses and lymphocyte subpopulations and function in osteomyelitis and septic arthritis

We investigated serum IgA, IgG, IgM and IgG subclass concentrations, complement activity, lymphocyte subpopulations, lymphocyte responses to mitogens and natural killer cell cytotoxicity in 15 children who had had osteomyelitis and septic arthritis and in a group of control subjects. IgG subclass concentrations below the fifth percentile for age occurred in 4 patients. We found isolated deficiencies of IgG1 and IgG3 and combined deficiencies of IgG2/IgG3/IgG4 and IgG2/IgG4. Concentrations of IgA and of IgG tended to be below the mean for age. The percentage of Leu-11+ cells was reduced in patients. Other immunological parameters studied were normal. These findings suggest that although most patients who have had osteomyelitis and septic arthritis do not have low immunoglobulin concentrations, impaired antibody production may be a predisposing factor in at least a few such children.     

Immunoglobulin G Subclasses and Lymphocyte Subpopulations and Function in Osteomyelitis and Septic Arthritis

ABSTRACT. We investigated serum IgA, IgG, IgM and IgG subclass concentrations, complement activity, lymphocyte subpopulations, Iymphocyte responses to mitogens and natural killer cell cytotoxicity in 15 children who had had osteomyelitis and septic arthritis and in a group of control subjects. IgG subclass concentrations below the fifth percentile for age occurred in 4 patients. We found isolated deficiencies of IgGI and IgC3 and combined deficiencies of IgG2/IgG3/IgC4 and IgG2/IgG4. Concentrations of IgA and of IgG tended to be below the mean for age. The percentage of Leu-11 + cells was reduced in patients. Other immunological parameters studied were normal. These findings suggest that although most patients who have had osteomyelitis and septic arthritis do not have low immunoglobulin concentrations, impaired antibody production may be a predisposing factor in at least a few such children.     

Anti-alpha-gliadin antibodies are not predictive of celiac disease in juvenile chronic arthritis

Some authors have recently reported an increased level of antigluten antibodies in rheumatoid arthritis, both in the adult and juvenile form. The real meaning of these antibodies is still unclear. We ascertained the levels of antigluten antibodies in a group of children with juvenile chronic arthritis to determine if these antibodies were linked with celiac disease and/or to increased intestinal permeability. In 18 of 53 patients (33.9%), the levels of antigluten antibodies (IgA or IgG) were higher than normal. No correlation was found between the increase in antigluten antibodies and the positive lactulose/ mannitol test, used for determining increased intestinal permeability. In all eight patients undergoing intestinal biopsy due to abnormal levels of antigluten antibodies (IgA class), intestinal mucosa was normal. In conclusion, our study shows that in patients with juvenile chronic arthritis, immunological response to gluten is neither related to celiac disease nor to increased intestinal permeability.     

Clinical findings and intestinal immunoglobulins in children with partial IgA deficiency.

We studied the intestinal morphology, and the jejunal and rectal immunoglobulins of 16 children with partial IgA deficiency, defined as serum IgA concentration more than two standard deviations below the mean for age, but higher than the lower limit of sensitivity of single radial immunodiffusion (0.02 g/l). Five of the patients had been treated with phenytoin, 2 had juvenile rheumatoid arthritis, 2 had ulcerative colitis and 5 had recurrent upper respiratory tract infections. The jejunal morphology was normal in every case. In 6 cases normalization of serum IgA occurred during the follow-up, while in one patient with ulcerative colitis the concentration fell below 0.02 g/l. In patients with recurrent infections, there was a decreased frequency of infections when the level of serum igA increased. In 4 patients, IgM-containing cells prodominated in both the jejunal and rectal mucosa, and IgM was increased in the intestinal juice. In 6 patients a significant increase in IgM-containing cells or a decrease in IgA-containing cells or both were seen in either the rectal or jejunal mucosa. There was no correlation between the number of IgA-containing cells in the intestinal mucosa and the serum level of IgA.     

IgA deficiency in children: A clinical study with special reference to intestinal findings

Clinical, immunological, and intestinal studies on 26 children with IgA deficiency in the age range 2 to 16 years are reported. 9 of these children were suffering from autoimmune disease, namely thyroiditis (5), thyrotoxicosis (1), rheumatoid arthritis (2), and probable Sjögren''s syndrome (1). The last-mentioned patient had defective cellular immunity. Altogether 11 patients were subject to recurrent respiratory tract infections. The symptomatology of the remaining patients was variable. In a boy with growth retardation, a chromosome anomaly was found, and endocrinological studies indicated total absence of growth hormone.In 21 patients IgA was undetectable, while 5 had trace amounts of IgA in their sera. IgG was raised in 11 patients, and one patient had low serum IgG. IgM levels were mostly normal. Precipitating antibodies to cow''s milk proteins were present in all but one serum.Small intestinal biopsy was performed on all patients. In 3 cases total villous atrophy was detected and these probably had coeliac disease, though malabsorption symptoms were not always evident. Disaccharidase assay of biopsy specimens revealed 2 cases of isolated lactase deficiency among 8 tested.Results show that the increased incidence of autoimmune disease reported in IgA deficiency in adults also holds true in children; i.e. that there is a raised incidence of coeliac disease with or without symptoms in IgA deficiency.     

幼年特发性关节炎患儿免疫学指标检测的意义

目的探讨幼年特发性关节炎(JIA)患儿体液和细胞免疫部分指的标变化及其临床意义。方法检测218例JIA患儿的免疫球蛋白(Ig)IgG、IgAI、gM,补体C3、C4,类风湿因子(RF),抗核抗体(ANA),抗双链DNA抗体(ds-DNA)及分化群(CD)CD3 、CD4 、CD8 及CD4 /CD8 值;对各亚型JIA与正常对照组CD3 、CD4 、CD8 、CD4 /CD8 测定值进行比较。结果各亚型JIA近半数患儿IgG、IgAI、gM及C3升高,RF阳性率5.2%,ANA滴度升高率11.1%,与附着点相关的关节炎(ERA)和少关节型人类白细胞抗原(HLA)-B27阳性率分别达100%、20%。各亚型JIA CD4 、CD8 水平与正常对照组比较有显著性差异,CD4 /CD8 值无显著性差异。结论JIA患儿存在明显的体液及细胞免疫功能紊乱。     

CLINICAL FINDINGS AND INTESTINAL IMMUNOGLOBULINS IN CHILDREN WITH PARTIAL IgA DEFICIENCY

Abstract. We studied the intestinal morphology, and the jejunal and rectal immunoglobulins of 16 children with partial IgA deficiency, defined as serum IgA concentration more than two standard deviations below the mean for age, but higher than the lower limit of sensitivity of single radial immunodiffusion (0.02 g/l). Five of the patients had been treated with phenytoin, 2 had juvenile rheumatoid arthritis, 2 had ulcerative colitis and 5 had recurrent upper respiratory tract infections. The jejunal morphology was normal in every case. In 6 cases normalization of serum IgA occurred during the follow-up, while in one patient with ulcerative colitis the concentration fell below 0.02 g/l. In patients with recurrent infections, there was a decreased frequency of infections when the level of serum igA increased. In 4 patients, IgM-containing cells predominated in both the jejunal and rectal mucosa, and IgM was increased in the intestinal juice. In 6 patients a significant increase in IgM-containing cells or a decrease in IgA-containing cells or both were seen in either the rectal or jejunal mucosa. There was no correlation between the number of IgA-containing cells in the intestinal mucosa and the serum level of IgA.     

早期急性白血病与类风湿性关节炎的鉴别诊断探讨

骨关节肌肉症状是许多小儿急性白血病（AL）的早期表现，有可能误诊为类风湿性关节炎（RA）。本文比较了误诊为RA的AL患儿与RA患儿的早期和确诊时的临床和实验室表现，发现AL组骨关节肌肉疼痛剧烈，关节不肿或轻微肿大，常为短暂性，胸骨压痛常见，RA组关节固定性持续肿大，单纯胸骨压痛罕见。AL组Hb的下降速度快，幅度大也与RA组有别；血小板减少和持续下降有利于AL的诊断，RA组则正常和增加而无下降。强调有经验的临床病理学家和血液学家多次观察血涂片的细胞形态非常重要，若有可疑，应即时作骨髓检查。特别指出使用电子血球计数仅而不作细胞形态学观察，有可能贻误诊断。     

Immunological aspects of juvenile rheumatoid arthritis

This article reviews the evidence from recent studies on immunological abnormalities associated with pathophysiologic mechanisms operating in three clinical subtypes of juvenile rheumatoid arthritis (JRA) (polyarticular, pauciarticular and systemic). The main discussion is focused on three hallmarks of immunopathological studies. First, abnormalities in phenotype and function of lymphocytes from peripheral blood and inflamed synovium are discussed. The aberrations of lymphocytes are elucidated by T and B cells expressing phenotypic cell-markers such as CD20, CD21, CD4, CD8 and DR in association with different subtypes and disease activity. The functional imbalance and impairment of T and B cells are mainly observed by abnormal proliferation and/or in vitro Ig production in response to mitogens and alloantigens. Second, because the appearance of rheumatoid factors (RF) in serum indicates that the pathogenesis of JRA may be based on the autoimmune mechanism, the prevalence of RF including IgM, IgA and IgG isotype, hidden IgM RF and cross-reactive idiotype RF, and their characteristic properties are discussed. Moreover, specific auto-antibodies (antinuclear antibodies and others) for JRA are illustrated in this paper. Third, the production of various pro-inflammatory cytokines resulting in the release of tissue-damaging chemical mediators is also discussed. This may play a central role in the generation of systemic inflammation and joint involvement in JRA.     

Monocyte bone degradation: in vitro analysis of monocyte activity in patients with juvenile rheumatoid arthritis

We examined the ability of the mononuclear phagocyte in vitro to degrade 45Ca-labeled bone particles to determine whether this assay allowed us to monitor disease activity in patients with juvenile rheumatoid arthritis. The monocytes from patients with juvenile rheumatoid arthritis receiving no anti-erosive therapy (n = 10) degraded significantly more bone than did cells obtained from normal controls (n = 10, P less than 0.001) or patients with juvenile rheumatoid arthritis receiving either gold thioglucose (n = 4, P less than 0.001) or D-penicillamine (n = 6, P less than 0.005). In two patients monitored for either 8 or 11 months, results of monocyte assays were found to parallel the clinical course. We conclude that in vitro monocyte bone degradation assays may provide a means of assessing joint activity in patients with juvenile rheumatoid arthritis. Further, this study and others indicate that mononuclear phagocytes are capable of causing erosive changes.     

Immunological Studies of the Placenta in Maternal Connective Tissue Disease

Maternal connective tissue disease is an important cause of second-trimester fetal loss. In order to assess the pathological changes in the placenta in maternal connective tissue disease, we reviewed the clinical histories and performed histologic and immunofluorescence studies on nine placentas: five from mothers with systemic lupus erythematosus (SLE), two from mothers with mixed connective tissue disease (MCTD), one from a mother with rheumatoid arthritis (RA), and one from a mother without prior known connective tissue disease. Excessive intervillous fibrin deposition and infarction were noted in all cases. Immunofluorescent and immunoperoxidase studies showed deposits of fibrinogen, IgG, IgM, IgA, and complement 3 (C3) localized to the trophoblast basement membrane (TBM). Electron microscopy documented thickening of the trophoblast basal lamina in three SLE placentas examined. The use of immunofluorescence may be enhanced further if antitrophoblast antibodies can be linked to placental compromise. Received June 11, 1997; accepted May 7, 1998.     

ANTI-IgG ANTIBODIES IN JUVENILE RHEUMATOID ARTHRITIS

ABSTRACT. Egeskjold, E.-M., Permin, H., Hørbov, S. and Graudal, H. (Rheumatism Research Unit of Aarhus University, Aarhus, Denmark). Anti-IgG antibodies in juvenile rheumatoid arthritis. Acta Paediatr Scand, 70:711,.–Sixty-two patients, 48 children and 14 adults, with juvenile rheumatoid arthritis (JRA) and 62 age and sex matched controls were studied for anti-IgG antibodies of the classes IgG, IgM and IgA by an indirect immunofluorescence method. 88 % of 48 children =≤16 years and in 64 % of 14 patients >16 years with JRA against 2 % of the controls. IgM anti-IgG occurred inIgG anti-IgG occurred in 4 % of the children, in 24 % of the adults and in 2 % of the controls. IgA anti-IgG occurred in 2 % of the patients and in none of the controls. The prevalence of IgG anti-IgG was the same in pauciarticular, polyarticular and systemic cases, whereas the titres were higher in polyarticular than in pauciarticular cases, and higher in children with a disease duration of more than 5 years. Higher titres were related to higher ESR and lower hemoglobin values. The relationship of higher titres to clinically active disease was not statistically significant. No relationship was found to age, sex, age at onset, or to the dureation of disease. The titres were not related to the concentrations of serum IgG or to the titres of antinuclear antibodies. IgG anti-IgG are common to all the clinical types of JRA, whereas antinuclear antibodies separate the systemic type from pauci- and polyarthritis. Their possible pathogenic significance must therefore be different.     

Selective deficit of IgA and infantile rheumatoid arthritis. Case reports

Three children with selective deficiency of serum IgA associated with oligoarticular juvenile rheumatoid arthritis (JRA) are presented. Before the appearance of JRA, all 3 children had shown frequently some respiratory infections. Indeed IgA deficiency may be asymptomatic or may cause a higher frequency of respiratory, gastrointestinal, allergic or autoimmune diseases, among which, JRA is one of the most important conditions.     

Rheumatoid rosette in juvenile rheumatoid arthritis

The rheumatoid rosette test was performed in 159 children. Positive results were found more frequently in juvenile rheumatoid arthritis when more than four joints were involved. It is not to be considered as a diagnostic test since `false positive'' tests occur in other diseases. The immunological significance of the rosette test is discussed.     

IgA nephropathy associated with a novel N-terminal mutation in factor H

Most patients with IgA nephropathy exhibit complement deposition in the glomerular mesangium. Certain cases of IgA nephropathy have been associated with reduced levels of complement factor H. A recent study could not demonstrate mutations at the C-terminal of factor H. We describe a novel heterozygous mutation in factor H, position A48S (nucleotide position 142 G > T, alanine > serine), detected in exon 2 of a 14-year-old girl with IgA nephropathy. The patient exhibited reduced levels of C3 and factor H, the latter suggesting that the mutation affected factor H secretion. The patient developed initial signs and symptoms of glomerulonephritis at the age of 9 years but presented again at the age of 14 years with weight gain, renal failure, nephrotic-range proteinuria and malignant hypertension. Blood tests suggested the development of microangiopathic hemolytic anemia (MAHA) but the renal biopsy was mostly indicative of chronic changes associated with IgA nephropathy as well as vascular changes associated with malignant hypertension. Immunofluorescence exhibited deposits of IgA, C3, and IgM. Screening of the factor H gene revealed, in addition to the mutation, three heterozygous hemolytic uremic syndrome -associated risk polymorphisms (−257 c/t, 2089 a/g, and 2881 g/t) which may have increased the patient’s susceptibility to the occurrence of MAHA triggered by malignant hypertension. The combined clinical picture of IgA nephropathy and MAHA may have been partly related to the alterations in factor H.     

Upper airway defence mechanisms

The nose is the airconditioner of the airways. Because normal breathing is through the nose, most airborne particles are filtered there; hence the nasal mucosa is the first line of defence against particles in the air. Pathogenic and non-pathogenic antigens continuously bombard the epithelium of the nasal airway. These antigens are mainly removed non-immunologically by the first defence layer of the mucosa, consisting of mucus, ciliated epithelial cells, glycoproteins/lysosymes. If the antigen passes this defence layer, specific and non-specific immunological defence mechanisms exist. The non-specific defence consists of phagocyting cells like neutrophils and macrophages and the complement activation. The specific defence mechanism (resulting in a specific immunological reaction in relation to a certain antigen) is formed by the antibodies, mainly secretory IgA and to a lesser extent IgG and immunocompetent cells in the nasal mucosa. Activation of the specific defence mechanisms may lead to inflammation which can be allergic. The intense co-operation of mechanical, aspecific and specific immunological defence results in a tightly controlled balance between a proper defence against pathogens and hypersensitivity. Failures in these defence mechanisms, or their co-operation, results in upper respiratory infection and/or allergy.     

Clinical impact of altered immunoglobulin levels in Henoch–Schönlein purpura

Background:  The aim of the present study was the identification of immunological features, present at the time of diagnosis, that would predict the severity of Henoch–Schönlein purpura and its outcome.
Methods:  A cohort study was carried out in a tertiary pediatric hospital of 69 children with Henoch–Schönlein purpura, in whom serum complement components C3, C4 and IgA, IgM, IgG were repeatedly determined.
Results:  During the acute phase of the disease in 54/69 patients (78.3%) immunological imbalances were observed. In 24/54 cases (44.4%) certain complications involving the kidneys and the gastrointestinal tract were noted as opposed to in 3/15 children (20%) without immunologic abnormalities. In 50/69 children (72.5%), elevated serum IgA was detected and 16 of them (32%) developed renal involvement while only 1/19 children (5.3%) with normal IgA concentration had renal involvement. Considering separately the group of 9/69 children (13%) with increased IgM and those with normal IgM levels (53/69; 76.8%), irrespective of IgA and IgG concentration, we found a comparable percentage of children who had both renal and intestinal involvement without, however, developing severe complications, which were exclusively seen in patients with increased IgA (5/7 children) and reduced IgM levels. Serum C3 fraction was elevated in 26 children (37.7%) and in 73% of cases it was associated with increased serum IgA values.
Conclusion:  Renal involvement was seen in 32% of children with increased IgA values. Most importantly, elevated IgA concentration along with reduced IgM levels was associated with higher prevalence of severe complications.     

Soluble thrombomodulin and antibodies to bovine glomerular endothelial cells in patients with Henoch-Sch?nlein purpura

AIM: To evaluate the clinical significance of soluble thrombomodulin and antiendothelial cell antibodies (AECA) in children with Henoch-Sch?nlein purpura. METHODS: Binding of serum AECA to bovine glomerular endothelial cells was evaluated by enzyme linked immunosorbent assay, cytotoxicity against glomerular endothelial cells by spectrophotometric assay, and soluble thrombomodulin concentrations by sandwich enzyme immunoassay. RESULTS: IgA AECA were detected in seven of 15 patients with Henoch-Sch?nlein purpura and nephritis, but were not detected in patients without nephritis or in controls. Patients with Henoch-Sch?nlein nephritis had raised titres of IgA AECA and serum thrombomodulin; severe proteinuria and renal histological changes were associated with raised titres of IgA AECA and raised serum thrombomodulin. No subjects had complement dependent cytotoxicity against glomerular endothelial cells. CONCLUSIONS: High titres of IgA AECA and raised serum thrombomodulin may be clinically useful markers of renal involvement in patients with Henoch-Sch?nlein purpura.     

Soluble thrombomodulin and antibodies to bovine glomerular endothelial cells in patients with Henoch-Sch?nlein purpura

AIM—To evaluate the clinical significance of soluble thrombomodulin and antiendothelial cell antibodies (AECA) in children with Henoch-Schönlein purpura.METHODS—Binding of serum AECA to bovine glomerular endothelial cells was evaluated by enzyme linked immunosorbent assay, cytotoxicity against glomerular endothelial cells by spectrophotometric assay, and soluble thrombomodulin concentrations by sandwich enzyme immunoassay.RESULTS—IgA AECA were detected in seven of 15 patients with Henoch-Schönlein purpura and nephritis, but were not detected in patients without nephritis or in controls. Patients with Henoch-Schönlein nephritis had raised titres of IgA AECA and serum thrombomodulin; severe proteinuria and renal histological changes were associated with raised titres of IgA AECA and raised serum thrombomodulin. No subjects had complement dependent cytotoxicity against glomerular endothelial cells.CONCLUSIONS—High titres of IgA AECA and raised serum thrombomodulin may be clinically useful markers of renal involvement in patients with Henoch-Schönlein purpura.     

Role of IgA in IgA nephropathy

IgA nephropathy (Berger disease) is defined by the dominant or codominant deposition of IgA in the renal mesangium. There is much evidence in vitro to suggest up-regulation of the IgA immune response in patients. Data from tonsillar and bone marrow-derived lymphocytes and from in vivo immunization studies indicate that the primary defect is an up-regulated systemic one, rather than mucosal IgA production. Several lines of evidence suggest that increased IgA production alone is inadequate to explain the pathogenesis of Berger disease. Murine models of IgA nephropathy indicate that local complement activation mediated by deposited IgG is essential for mesangial cell proliferation and subsequent renal injury. Circulating immune complexes from patients with Berger disease contain IgA and IgG within the same lattice. In vitro studies of model immune aggregates containing various mixtures of IgA and IgG indicate that the IgG is the site of complement activation and fixation. The IgA in the aggregate actually inhibits both complement activation and binding to erythrocyte complement receptor CR1. This effect of IgA may prevent effective immune complex clearance. In future studies, more emphasis should be placed on the roles of IgG and complement in the pathogenesis of IgA nephropathy.