T. Ozawa

Suppression of immunoglobulin production of lymphocytes by intravenous immunoglobulin

The proliferative responses and the immunoglobulin production of peripheral blood mononuclear cells to pokeweed mitogen were dose-dependently suppressed by sulfonated intravenous immunoglobulin (IVIG), polyethylene glycol-treated IVIG, pH 4-treated IVIG, or human γ-globulin, but they were not or only slightly suppressed by human serum albumin or pepsin-treated IVIG. Moreover, the suppression of immunoglobulin production by sulfonated IVIG, polyethylene glycol-treated IVIG, or pH 4-treated IVIG was seen in the cases in which B cells preincubated with IVIGs were cocultured with T cells and monocytes preincubated with or without IVIGs and in the cases in which monocytes preincubated with IVIGs were cocultured with T cells and B cells preincubated with or without IVIGs. However, in the cases in which only T cells were preincubated with IVIGs, immunoglobulin production was not suppressed. The suppression of the monocyte function by IVIGs tended to be less than the suppression of the B-cell function by IVIGs. Moreover, the suppression by IVIGs was blocked by antihuman IgG Fc. Our results suggest that IVIGs suppress the immunoglobulin production of lymphocytes through suppression of the B-cell function and the antigen presenting-cell function by attachment of IVIGs to Fc receptors of B-cell membranes and antigen presenting-cell membranes.

Reduced secreted μ mRNA synthesis in selective IgM deficiency of Bloom's syndrome

Serum IgM concentrations were low although serum IgG and IgA concentrations were normal in both our patients with Blooms syndrome. Although the percentages of surface Ig‐earing cells were not reduced, the numbers of Ig‐ecreting cells were markedly reduced. The membran‐ound μ(μm) and secreted μ (μs) mRN As arc produced from transcripts of a single immunoglobulin μ gene by alternative RNA processing pathways. The control of μs mRNA synthesis depends on the addition of poly(A) to μs ‐erminal segment. In both patients, μ mRNA was well detected but μs ‐erminal mRNA was scarcely detected, suggesting that μ mRNA was well transcribed but μs mRNA was not. There was, at least, no mutation or deletion in the μs ‐erminal coding sequence, the RNA splice site (GG/TAAAC) at the 5’ end of μs ‐erminal segment and the AATAAA poly(A) signal sequence in both patients. Our results suggest that selective IgM deficiency in Blooms syndrome is due to an abnormality in the maturation of surface Ig‐earing B cells into Ig‐ecreting cells and a failure of μs mRNA synthesis. Moreover, reduced μs mRNA synthesis may be due to the defect on developmental regulation of the site at which poly(A) is added to transcripts of the μ gene.

Improvement of food‐sensitive atopic dermatitis accompanied by reduced lymphocyte responses to food antigen following natural measles virus infection

Five patients with atopic dermatitis (AD) who were sensitive to hens egg were observed before and after natural measles virus infection. Within 4 weeks of natural measles virus infection, the eczematous lesions clearly improved in four of the five patients in whom neither offending foods were eliminated, nor anti‐allergic drugs, systemic steroids and steroid ointment administered. This was accompanied by reduced proliferative responses of peripheral blood mononuclear cells (PBMCs) to ovalbumin (OA). Another patient showed a transient improvement of AD symptoms, from severe to mild, and thereafter returned to severe accompanied by increased proliferative responses of PBMCs to OA. Radioallergosorbent test (RAST) scores for hens egg in all five patients did not change in each level in each patient, except the transiently decreased RAST scores for hens egg in one patient, after the infection. Thus, in patients with AD who are sensitive to food, the improvement of AD symptoms that appeared within 4 weeks of natural measles virus infection was related to reduced proliferative responses of PBMCs to the food antigen following the infection.

DNA MUTATION INDUCED IN THE SEQUENCE UPSTREAM OF THE SECRETED MYU C‐TERMINAL CODING SEQUENCE BY ULTRAVIOLET IRRADIATION IN THE CELL LINE OF BLOOM'S SYNDROME

Selective IgM deficiency is commonly found in Blooms syndrome (BS). We reported that membrane‐bound μ (μ m) mRNA was well transcribed but secreted μ (μ s) mRNA was not, although there was no mutation or deletion in the sequence including the (is C‐terminal coding sequence in the patients with BS. Furthermore, we have shown previously, preferential damage to IgM production by ultraviolet (UV) irradiation of the cells of the patient. In the study described here, mutation in the sequence which is upstream of the 5’ end of the μ s C‐terminal coding sequence was induced by UV irradiation in the lymphoblastoid cell line (LCL) of BS patient. These results suggest that abnormal repair of DNA damage is present in this LCL, and that preferential damage to IgM production by UV irradiation in this LCL may be due to the abnormal repair of DNA damage.

Expression of the Alpha‐Chain Gene in Heterogeneous IgA Immunodeficiency

Five heterogeneous IgA‐immunodeficient patients were analysed for expression of the α‐chain gene. The number of surface IgA‐bearing B cells was low in four patients Southern blot analysis indicated no deletion of immunoglobulin structural genes coding for Cα or α switching‐region genes. The number of surface IgM and IgA double‐bearing B cells increased in some patients. Addition of recombinant tnterieukin 4 (rIL‐4). rIL.‐5. and rIL‐6 to the normal B cells enhanced IgA production. However. B cells of the patients showed no or one‐third lower IgA production in response to these lymphokines, even though there was proliferation ill 4, rIL ‐5, and rIL‐6 induced low or no expression of α mRNA of the patients B cells These results suggested that the patients lacked B cells able to produce transcripts for the IgA heavy chain, and that some patients’B cells might be defective at the switch‐recombination process from u to a or from μ to α or from μ and α to α.

Common variable immunodeficiency with increased surface IgM-positive double-bearing B cells.

We report a case of common variable immunodeficiency (CVI) that shows low levels of IgG and IgA, but a normal quantitative or qualitalive level of IgM. T‐cell functions were not disturbed. Increased numbers of surface IgM (sIgM) and sIgD, sIgM and sIgA, sIgM and sIgA double bearing B cells were observed as compared with a control. No IgG and IgA induction upon stimulation with Staphylococcus aureus Cowan I (SAC)and recombinant interleukin‐2(rIL‐2), or pokeweed mitogen (PWM) and rIL‐4 or rIL‐6 was observed, although there was proliferation. Although; μ mRNA was expressed as much as in a healthy control, transcription of γ mRNA and α mRNA was very low. Furthermore, no enhanced effects of γ mRNA and α mRNA were recognized upon stimulation with rIL‐4 and rIL‐6. These results suggest that the patients B cells might be detective at the switching process from μ, μ and δ, μ and γ to γ or μ and α to α.

A case report of a 9-year old boy with polyarteritis nodosa in which a combination therapy of corticosteroids and a photosensitive dye Platonin was effective

Polyarteritis nodosa (PN), characterized by vasculitis of medium and small sized arteries, is uncommon in children. This disease is thought to be concerned with some abnormal immune responses. Platonin (4,4′-dimethyl-3,3′-di-n-heptyl-8-[2-(4-methyl-3-n-heptylthiazole)]-2,2′-dicar bocyanine diiodine) is one of the photosensitive dyes of trithiazole pentamethine cyanine. It has been reported that platonin stimulated suppresser/cytotoxic T cells, but suppressed B cells. In clinical observations, platonin is shown to be efficacious for rheumatoid arthritis and juvenile rheumatoid arthritis. In this study, a Japanese boy (9-year-old) with PN was given platonin in combination with prednisolone. Prednisolone was gradually tapered under a cover of platonin. As a result, the relapse has not been exhibited for a long time (72 months). There were no adverse side effects during long term administration of medication.

a wild-type μs C-terminal gene is expressed in Bloom's syndrome cells

Selective IgM deficiency is found commonly in patients with Blooms syndrome (BS). Serum IgM concentrations were low though serum IgG and IgA concentrations were normal in both patients with BS included in the study. In a previous study the authors showed that selective IgM deficiency in BS is due to an abnormality in the maturation of surface IgM‐bearing cells into IgM‐secreting cells and a failure of secreted μ (μ s) mRNA synthesis. The membrane‐bound μ (μ m) and μ s mRNA are produced from transcripts of a single immunoglobulin μ gene by alternative RNA processing pathways. The control of μ s mRN A synthesis depends on the addition of poly(A) to μ s C‐terminal segment. The study described here demonstrated that there was no mutation or deletion in the sequence including μ s C‐terminal coding sequence, the RNA splice site (GG/TAAAC) at the 5’ end of μ s C‐terminal segment, and the AATAAA poly(A) signal sequence, and second GT‐rich element immediately down‐stream of the cleavage site in both patients.

Kinetics of hypogammaglobulinemia in patients with common variable immunodeficiency

We investigated the production of immunoglobulin (Ig) in six patients with common variable immunodeficiency and analyzed the courses of their levels of serum Ig for a period of 8–13 years. In all patients, levels of serum IgM, IgG and IgA were markedly low at the first examination, except for the IgM level in one patient. Improvement of serum Ig levels was observed in the patients in whom Ig production of non‐T cells at the first examination and Cμ gene expression had been detected to a slight degree, but serum Ig levels remained low in the patients in whom Ig production of non‐T cells and Cμ gene expression had not been detected. Our results suggest that some hypogammaglobulinemia in common variable immunodeficiency develops or improves with age.