The influence of daily administration of interferon-β (HuIFN-β) on the NK and ADCC activities and cell surface markers of lymphocytes or monocytes in multiple myeloma were studied.
NK and ADCC activities were measured against ⁵¹Cr labelled target cells (K-562 cell line, Raji cell line and autologous myeloma cells) using 4h-⁵¹Cr releasing method. Surface antigens of lymphocytes and monocytes were analysed by flow cytometry (Spectrum III, Ortho Diagnostic Systems) using monoclonal antibodies.
The results are as follows:
1) After administration of HuIFN-β, autologous NK activity (against autologous myeloma cells) showed a transient decrease, whereas autologous ADCC activity tended to increase within 4 days.
2) Allogenic NK activity for K-562 cell line decreased transiently, followed by a period of constantly high levels, after the fourth day, whereas allogeneic ADCC activity for Raji cell line showed a similar pattern for 4 days, but thereafter recovered to pre-administration levels.
3) Leu M1 and Leu M2 positive cells in the monocyte area of flow cytometry showed a substantial increase after daily administration of interferon, and the OKT4 positive rate in the lymphocyte area showed a transient increase 6 hours after administration of interferon.
4) It was suggested that autologous ADCC activity, which increased after administration of interferon, is related to positive cells of Leu7 and OKM1 (in lymphocyte area), and that autologous NK and allogeneic ADCC activities, which showed a transient decrease, are related to Leull and OKM1 (in monocyte area).
5) Immunological response patterns were not influenced by 4 weeks' daily administration of HuIFN-β.
From the above results, it may be speculated that daily administration of interferon-β has an indirect effect on myeloma cells, through activated lymphocytes and/or monocytes.

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The immunological abnormality of systemic lupus erythematosus (SLE) is characterized by polyclonal B cell activation. Whether polyclonal B cell activation is caused by B cell abnormality or effect of B cell stimulatory factors (BSF) were investigated in this study. B cell function of SLE patients and normal individuals were measured by three methods, 1) Staphylococcus aureus Cowan I (SAC) response, 2) BCGF response and 3) BCGF response after SAC stimulation. There was no significant difference in B cell function among three groups (active SLE group, inactive SLE group and normal individuals group). Supernatants of PHA stimulated T cell and SAC stimulated B cell contained BCGF and BCDF activities. T cell derived BCGF and BCDF activities in active SLE patients revealed higher than in inactive SLE patients and normal individuals. There was no significant difference among these group in B cell derived BCGF like activity, but BCDF like activity revealed higher in active SLE patients than in inactive SLE patients and normal individuals. High level of BCGF and BCDF like activities were shown also in sera of active SLE patients found than in those of other two groups. As mentioned above, these results suggested that polyclonal B cell activation in SLE patients might be chiefly caused by increased T cell derived BCGF and BCDF activities, and B cell derived BSF respond to B cell as supportive factors.

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Fifty five Japanese patients with systemic lupus erythematosus (SLE) were determined for HLA class I (HLA-A, -B and -C), II (HLA-DR and -DQ) and III (C2, C4 and Bf allotypes) antigens. The antigen frequencies were compared with those of 420 (class I and II) and 55 (class III) normal Japanese controls. As a result, the followings were clarified first on Japanese SLE.
1. Japanese SLE was associated with C4A0, a C4 allotype of HLA class III. This was the first HLA allotype common in Japanese and Caucasian SLE.
2. The haplotype with linkage disequilibrium in Japanese Patients with SLE was the haplotype Bw62-C4A0-DR4.1, which was quite different with Bw56-C4A0-DRw12 or w6 commonly seen in normal Japanese controls.
3. SLE diagnosed clinically seemed to be hetorogenous pathogenetically.

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Specific reference is applied to the functional significance of gravidity, a process being equivalent to the isogeneric transfer that takes place under anomalous immunological situation, and what is specifically discussed here is the behavior of NK-activity observable throughout gravid period, some of the distinctive facts it offers being illustrated as follows:
1) NK-activity began to fall with the beginning of gravidity, decreasing further with time, until it regained subsequent to delivery as high a level as of non-pregnant subject;
2) The findings that removal of adherent cells and administration of indomethacin has been incidentally shown to stimulate NK-activity under gravidity, positively suggest that loss of NK-activity may be attributable to prostagrandin produced by monocytes;
3) It is commonly agreed that γIFN would normally give rise to a stimulation of NK-activity. This observation, however, was found to be not absolutely true while in gravidity, whereas NK-activity reacted against γIFN 3 weeks after delivery as if the mother were non-pregnant. In addition, removal of adherent cells could entail none of change in sensitivity of NK-activity to γIFN. Altogether, it has been shown that adherent cells would not be responsible to the reduced reactivity to γIFN under gravidity;
4) In sharp contrast, against rIL-2 NK-activity, either of pregnant-or non-pregnant subject, invariably behaved positively.

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Sjögren's syndrome (SS), an autoimmune exocrinopathy, is characterized by polyclonal B cell activation and association of monoclonal B cell lymphoma. We therefore studied possible involvement of EBV in the pathogenesis of SS. EBV is known to be a polyclonal B cell activator and an oncogenic virus. The titer of serum antibody of IgG class against viral capsid antigen (VCA) was significantly elevated in SS sera. Serum anti-VCA antibody of IgM class was also significantly increased in titer in SS. Ten out of 37 SS sera had titers of both IgG and IgM anti-VCA antibodies suggesting reactivation of EBV in vivo. These cases had significantly enhanced level of serum IgG compared to SS patients without reactivation. Excretion of EBV from the oropharynx was frequently observed in SS (86%) compared to normal controls (33%). SS patients with increased anti-VCA antibody in the sera tended to be EBV excretors. Furthermore, we have successfully established B cell lines from the peripheral blood of SS patients but not from normal controls, when peripheral blood mononuclear cells were cultured without stimulation. These cell lines not only expressed EBV nuclear antigen (EBNA) but also excreted large amount of EBV in the culture.
These data might suggest possible involvement of EBV in the pathogenesis of SS.

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Neutrophils from 25 elderly persons (70 to 80 yr.) and from 15 young persons (<50 yr.) were investigated for their ability to produce chemotactic activity, phagocytic activity and oxygen intermediates (O_??_, H₂O₂, OH• and chemiluminescence). Neutrophils from old donors produced less chemotactic activity than did neutrophils from young donors as defined by either agarose plate method or Boyden chamber method (p<0.001). In contrast, phagocytic activity and production of oxygen intermediates by neutrophils from young and old donors were comparable. The selective failure in the chemotaxis of neutrophils associated with aging could contribute, at least in part, to the increase with age in the incidence of infectious diseases.

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Natural killer (NK) cells have been thought to play a primary role in preventing neoplasia from the development. Because of the increase with age in the incidence of neoplasia, one can expect impaired NK activity in aged humans. To test this hypothesis, NK activity from young and old persons has been measured. Increase in NK activity was demonstrated in groups aged 71 to 75, 76 to 80 and 81 to 85, although groups of 65 to 70 years and more than 86 years showed a comparable NK activity to that in young persons (18 to 50 years). The difference in observed NK activity could not be attributed to differences in percentage of NK cells in the blood from old and young persons. Increase with age in the NK activity may make up the decline of immunologic competence with age for maintaining normal immune system homeostasis.

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Several different approaches have been used for assessment of the mechanisms of B cell activation. In normal subjects, the circulating B cell pool contains B cells at various stages of activation. The resting B cells can be induced by T cell-independent B cell mitogen, Staphylococcus aureus Cowan I (SAC) to undergo proliferation. The partially activated B cells, when provided with adequate T cell help, can proliferate and differentiate into immunoglobulin (Ig)-secreting cells under the influence of either SAC or pokeweed mitogen (PWM). The fully differentiated B cells are represented by the numbers of cells in the peripheral blood that secrete Ig spontaneously.
We evaluated B lymphocyte function in 24 elderly (mean 79.3 yr.) and 14 young (mean 24.5 yr.) persons. Lymphocytes from elderly persons incorporated significantly less tritiated thymidine as compared with lymphocytes from young persons when stimulated with SAC. Moreover, the elderly, but not young, persons were found to have elevated numbers of cells spontaneously secreting Ig. However, lymphocytes from elderly persons stimulated with either SAC or PWM displayed Ig production equal to young persons. These results in elderly persons are consistent with polyclonal B cell activation in vivo, as can be seen after certain viral infections and in some autoimmune diseases. The potential role of age-related B cell abnormalities in the increase with age in the incidence of infections, neoplasia, immune deficiency, and diseases that may be mediated by immune complexes is discussed.

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Brochoalveolar lavage (BAL) were performed in 28 patients with sarcoidosis and in 31 normal subjects. In control subjects, the numbers of mononuclear cells and macrophages in smokers were significantly increased in comparison to nonsmokers (p<0.001 in each cases), but the numbers of lymphocytes were not.
In both smoking and nonsmoking untreated sarcoid patients, the proportion and number of lymphocytes were significantly increased compared to corresponding controls (p<0.05, p<0.001). The number of lymphocytes in patients not receiving prednisolone were not significantly increased than patients who were receiving prednisolone. No difference in numbers of lymphocytes was found between smoker and nonsmoker patients. BAL lymphocytes were identified as T lymphocytes (88.9±6.2%). Furthermore, untreated patients had significantly higher percentages of OKT-4 (+) T helper cells and significantly lower OKT8 (+) T suppresser cells within the alveolar lymphocytes population than that of normal nonsmokers (p<0.01 in each cases). Alveolar lymphocytosis is significantly correlated with the activity of lymphocyte blastogenesis induced by Propionibacterium acnes (p<0.01), and the ratio of OKT-4 (+) cells to OKT-8 (+) cells correlated with the activity of serum angiotensin-converting enzyme (p<0.05). However, neither the radiological stage nor the degree of Gallium-67 uptake in lung parenchyma was related to the lymphocyte number and the ratio of OKT-4/OKT-8 in BAL fluids.
The lymphocytosis of the bronchoalveolar space indicates the disease activity at the site of pulmonary space, and Propionibacterium acnes may play some role in the induction of the pulmonary lymphocytosis in sarcoidosis patients.

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With a view to define inherent tendency in activity of lymphokine activated killer (LAK) cell during pregnancy a series of test has been conducted with consequently evolved results quoted in the following summary;
1) In an extensive program of test there was a marked fall in activity of LAK significantly over the period from initial-to third trimester (p<0.01). It, however, rapidly recovered at the occasion of delivery until consequent difference has become no longer distinctive when compared to the equivalent of non-pregnant subject.
2) Another research directed to a possible influence of adherent cells and pregnant serum on the LAK activity which might possibly account for the loss of LAK activity, gave a conclusive evidence to support that both factors would give none of influence on the LAK activity.
3) Further study through flow cytometry on the behavior of lymphocyte subsets (OKT3, OKT4, OKT8, Leu7, Leull, OKIal and OKM1) under cultivation made with added interleukin 2 (IL-2) did show none of difference between pregnant-and non-pregnant subjects. From this fact it may be retrospectively inferred that loss of LAK activity during pregnancy would be attributed to dysfunction rather than to reduced number of LAK cells.
4) A factor to suppress IL-2 production capability of peripheral blood lymphocytes under PHA stimulation was identified in the serum of pregnant subjects, whereas it was not the case with the subjects during puerperal phase. With the above decisive fact it has been shown convincingly that induction of LAK activity during pregnancy would have been suppressed by etiological mechanism involving both loss of IL-2 production and dysfunction of LAK cells, viz. an immunological environment helpful to maintain pregnancy may have been thereby provided for.

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Peripheral blood lymphocytes from patients with systemic lupus erythematosus were compared with those of normal donors for their ability to perform antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC activity was significantly decreased (p<0.001) in active SLE. Correlations appear to exist between either disease activity, CH₅₀ or lymphocyte counts, and ADCC activity. There was no apparent relationship between ADCC activity and the level of corticosteroid administered. Also, no significant correlation was demonstrated between ADCC activity and the levels of circulating immune complex (CIC).
Sera from patients with SLE inhibited ADCC activity of the normal lymphocytes. A close relationship was observed between the inhibitory effect of SLE sera on the ADCC of the normal lymphocytes and CIC levels. Sera containing CIC inhibited ADCC of the autologous lymphocytes from the patients. No correlation was observed between ADCC activity and the serum-mediated inhibition of ADCC of normal lymphocytes. These results suggest that the decreased ADCC activity in SLE patients is partly due to the killer cell dysfunction as well as to the suppressive effect of CIC on the ADCC.

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We have experienced 2 cases of Graves' disease associated with anti-thyroid hormone auto-antibodies. Case 1: a 24-year-old pregnant woman was found to have exacerbation of Graves' disease of which she had been diagnosed when she was 10 years old. She was treated with propylthiouracil (PTU, 450mg/day) since March 26, 1985 when intra-uterine fetal death was found. Since serum total T₃ (TT₃) levels had been high even long after abortion in the face of normalization of total T₄ (TT₄), free T₄, and thyrotropin (TSH), presence of anti-thyroid hormone antibodies was suspected. Addition of labelled thyroid hormone to her serum followed by precipitation of γ-globulin fraction with 12.5% of polyethylene glycol showed an increased binding of ¹²⁵I-T₃ or ¹²⁵I-T₄r being 19.3% or 11.0%, respectively, to her serum γ-globulin fraction. Scatchard plot of anti-T₃ antibodies in her serum was analyzed in two components; one with a higher affinity constant (5.4×10⁷ M^-1), and the other with a lower affinity constant (1.0×10⁶ M^-1). Case 2: a 16-year-old female had been diagnosed as Graves' disease when she was 15 years old and had been treated with MMI for a year. By the treatment, she became physically euthyroid, and serum total thyroid hormone (TT₃, TT₄) levels declined to the normal level. However, since free thyroid hormone (FT₃, FT₄) levels showed unusually high levels, presence of anti-thyroid hormone antibodies in her serum was suspected. Her serum γ-globulin bound 34.5% and 12.2%, respectively, of ¹²⁵1-T₃ and ¹²⁵I-T₄. Scatchard plot of anti-T₃ antibodies in her serum was analyzed into two components; one with a higher affinity constant (2.4×10¹⁰ M^-1), the other with a lower affinity constant (3.1×10⁹ M^-1). Although further characterization of anti-T₄ antibodies in both cases has not been done, from the binding data of ¹²⁵I-T₄ to both sera, in addition to anti-T₃ antibodies, both cases were considered to have anti-T₄ antibodies. Our present cases indicate that it is clinically important to bear the presence of anti-thyroid hormone antibodies in mind to account for the possible error in measuring T₃ or T₄ by RIA. In the case that RIA results give unexpectedly high or low T₃ and/or T₄ value, the presence of autoantibodies should be considered first and a test for them is recommended.

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We described here a 27-year-old patient with selective IgA deficiency associated with three organ-specific autoimmune diseases; myasthenia gravis, autoimmune hemolytic anemia and autoimmune thyroiditis. This is the first report which documents so many associated autoimmune diseases in a patient with immune deficiency of this type, although the association of the disease with various autoimmune diseases has been described.
Serum IgA levels were less than 5mg/dl in the patient, and serum anti-IgA antibodies were detected at high titer. Furthermore, we could detect IgG, IgA, IgM and complement components on patient's erythrocytes by direct Coombs' test, and the presence of IgA on the erythrocytes were also confirmed by enzyme-linked immunosorbent assay using the eluate from erythrocytes.
Following to thymectomy undertaken for the management of myasthenia gravis, septicemia and hemolytic attack had developed in the patient. These complications were successfully treated with antibiotics and prednisolone, 60mg daily. No definite increase in serum IgA levels was observed during the treatment, although both myasthenia gravis and autoimmune hemolytic anemia were improved remarkably. Pathologically, patient's thymus was moderately involuted and contained lymphoid follicles. The thymectomy was considered to be effective for the management of myasthenia gravis in the patient based on 30 month-observation after the thymectomy.
The patient's salivary IgA were detected, but its concentration was low as compared with that of healthy controls. Surface IgA-bearing B lymphocytes were detected in the peripheral blood, whereas intracytoplasmic IgA synthesis was not demonstrated in the peripheral blood lymphocytes cultured with PWM.
We believe that this case report provides further considerations, clinically and immunologically, for the understanding of selective IgA deficiency and its associated diseases.

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We describe three females with systemic lupus erythematosus (SLE) who developed alveolar hemorrhage. Although they did not show any episodes of bleeding from the lung at first, bronchoscopy was performed in two of the three cases. The diagnosis of alveolar hemorrhage was made based upon the bloody bronchoalveolar lavage fluid and the transbronchial lung biopsy. Electron-dense deposits were identified in the alveolar basement membrane. These two patients responded well to the pulse-steroid therapy. This rare complication of SLE usually develops insidiously but rapidly, and its prognosis is extraordinarily poor. Only two autopsy cases have been reported in Japan. We emphasize the importance of bronchoscopy for the early diagnosis, and intensive respiratory care for the treatment of alveolar hemorrhage in SLE patients.

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