Biomedical subjects
Publications and source records attributed to E Möller.
Neonatally induced fully tolerant mice possess cytotoxic effector cells, specific for the tolerizing antigens, which can be induced by polyclonal T cell activators in vivo (Con A) on in vitro (poly A:U). Therefore, clonal deletion of specific effector cells is eliminated as the mechanism by which skin grafts are retained in tolerized mice.
Con A is known to activate T cells to proliferation and the development of effector cells. Conflicting reports have been published as to the need for accessory cells in the T-cell response induced by Con A. We have found that the proliferative response in purified mouse spleen T cells induced by various doses of Con A requires different culture conditions and helper cells. The Con-A-induced response induced by optimal and high concentrations of the ligand requires the presence of either serum or adherent cells obtained from the peritoneal cavity or the spleen. For induction of a proliferative response by low doses of Con A both serum and helper cells must be present. The T-cell response to suboptimal concentrations of Con A is further characterized by the fact that the presence of an Ia-positive cell is required. Removal of Ia-positive cells from purified T cells results in a loss of the response of remaining cells to low doses of Con A but has less effect on the response induced by higher concentrations of the activating ligand. The possibility that distinct subsets of T cells are responding to low and high concentrations of Con A will be discussed.
In a haemolytic plaque assay staphylococcal strain Cowan 1 was shown to induce polyclonal antibody secretion in human blood lymphocytes, whereas Haemophilus influenzae and Escherichia coli gave low responses. Diplococcus pneumoniae and haemolytic streptococci generally did not activate blood cells. All five bacteria could activate spleen, tonsil and adenoid cells both to polyclonal Ig secretion and increased DNA synthesis. Thus blood cell reactivity does not necessarily reflect the response pattern in other lymphatic organs. The adenoid was shown to contain lymphocytes more responsive to bacteria normally residing in nasopharynx than cells residing in other lymphatic organs. On the other hand, spleen and mesenteric lymph node contain a subpopulation of cells highly responsive to bacteria such as Escherichia coli normally residing in the bowel. Therefore, we conclude that there exists a functional compartmentalization of lymphocytes in distinct secondary lymphoid organs.
Lipopolysaccharides from E. coli (LPS) stimulated increased DNA synthesis and high-rate antibody secretion in human lymphocytes from blood and spleen. Peak DNA synthesis by 10 or 100 microgram/ml LPS was seen on day 6 for blood lymphocytes. Using 500 microgram/ml of LPS the peak response was reached on day 5 and with 0.1--1 microgram/ml the maximal stimulation was on day 7. For spleen cells LPS 100 microgram/ml gave a peak stimulation on day 4 or 5. Antibody secretion, measured as plaque-forming cells (PFC) against fluorescein isothiocyanate-coupled sheep erythrocytes in a haemolysis-in-gel assay, was maximal on day 5 in blood lymphocytes and on day 3 or 4 in spleen cells. The highest cell viability and antibody secretion after stimulation with LPS was obtained in 16 mm diameter multiwell plates usng 2.5 x 10(6) cells in 1 ml of medium containing 10% AB serum absorbed with SRBC. Feeding of cultures was essential for stimulation of blood lymphocytes but not for spleen cells.
Skin fibroblasts derived from persons who had been HLA-typed by conventional lymphocytotoxocity tests were subjected to HLA-typing by the mixed hemadsorption (MH) test. The agreement between the two methods was good, provided sera for the MH test were carefully selected. Minor discrepancies found in this study can probably be corrected by further serum selection. There was no difficulty in typing late passages of cultured diploid cells (22 doublings) and in fact it was easier to type a culture at the 33rd doubling than at the 11th. Thus no signs of disappearance of HLA-antigens were seen in these tests.
An HLA--D homozygous typing cell -- MS -- was found to induce typing responses with a phenotype frequency of 7% tested in a panel of 202 random individuals. All but two of these were positive for HLA--Dw7, which implies that the MS cell defines a split of Dw7. The new subgroups, MS, is associated with B12. Three individuals positive for MS but lacking Dw7 were found to be B13 positive. The relationship of the MS specificity to HLA--Dw11 has yet to be defined.
HLA-A, -B, -C and -D antigens were determined in 54 male Myasthenia Gravis patients. A significant increase of the B8 antigen frequency was found among patients with an onset of the disease before the age of 35. No significant increase was found among the D antigens. In a combined male and female material with an early age at onset, thymic hyperplasia was correlated to the presence of HLA-B8.
In three families with hereditary ataxia, where the inheritance pattern was autosomal and dominant, HLA antigens were determined in 25 members. In two of the families, HLA linkage of disease was suggested, whereas in the third family, the data did not directly support this concept, since two recombinational events between the postulated locus for disease and the HLA region had to be assumed. However, with this assumption, our data are compatible with those of one family described recently (Jackson et al. 1977) implying the presence on the sixth chromosome, outside the HLA region, of a locus that determines the development of spino cerebellar ataxia (SCA). Further tests with definition of enzyme markers will have to be performed before conclusions as to HLA linkage of a postulated SCA gene can be made.
Forty patients with myasthenia gravis were HLA tissue typed and the amount of anti-acetylcholine receptor protein antibody determined. Sera from seven patients were tested for antibody titer by repeated determinations and the serum concentration was found to be stable. Patients with thymoma had higher titers than patients with normal thymus histology or hyperplasia. Individuals with thymoma lacking HLA-B8 were found to have a higher concentration of antibodies than HLA-B8 negative individuals with hyperplasia. No statistically significant differences were obtained when comparing the amount of antibody in HLA-B8 positive and negative individuals. Titers in patients subjected to thymectomy more than 8 years before sampling did not deviate from those in non-thymectomized myasthenics.
Virus-induced proliferation of cerebrospinal fluid (CSF) lymphocytes and blood lymphocytes was studied in patients with mump meningitis and in patients with aseptic meningitis of other etiology. In four out of five patients with mump meningitis the proliferation of CSF lymphocytes after mumps virus stimulation was higher than obtained with the corresponding number of blood lymphocytes. No proliferation was registered when lymphocytes from patients with other aseptic meningitis were stimulated with mumps virus. These data indicate the occurrence in CSF of lymphocytes specifically sensitized against mumps virus in patients with mumps meningitis.
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The leukocyte migration inhibiton test was used in multiple sclerosis patients and in healthy controls for investigation of sensitization of blood lymphocytes against preparations of measles virus, mumps, NDV virus, and PPD. Regardless of antigen used, no significant differences were found between the groups. There was a strong correlation between the leukocyte migration inhibition obtained with measles virus antigen and with PPD. The leukocytes from MS patients as well as from healthy controls showed a significantly more pronounced inhibiton when a Tween 80 and ether-treated preparation of measles virus was used, compared with the whole measles virus antigen. No correlations were found between the degree of leukocyte migration inhibition and the antibody titers against different components of measles virus in individual samples.
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The mitogenic response of blood lymphocytes from twelve patients with B-cell CLL and seven healthy controls was investigated. All patients were untreated and had a typical B-cell dominance in their peripheral blood. The patients demonstrated a scattered response pattern with a higher variance than in the control group. We demonstrated examples of stimulation of DNA-synthesis by polyclonal B-cell activators (PBA) as well as inhibition. The variable pattern between the patients might result from a malignant transformation of cells originating from different lymphocyte subpopulations in different patients. Thus PBA studies of lymphocytes from CLL patients might be a valuable tool in characterizing further this clinically variable disease at the cellular level.
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This family consists of forty-eight subjects, all of whom have been examined with regard to the presence of psoriasis and nearly all for the presence of arthritic lesions (sacroiliitis and peripheral arthritis). All the members have been tissue-typed not only for HLA-A, B and C locus products but also for D locus products. This has enabled us to study the entire HLA chromosomal region. In the family concerned we have found that those subjects haploidentical with the proband have, to a very large degree, either one or all clinical manifestations, which demonstrates a close genetic relationship between joint (especially sacroiliitis) and cutaneous manifestations. These findings prompt us to repeat our previously made proposal about different phenotypic expressions of the same genotype. In this family study the disease-associated haplotypes did not contain the genes for B13, 17 or 37 antigens which are known to occur frequently in psoriatic patients. However, not all psoriasis patients have these antigens. Despite that, we believe that the gene(s) which increase the likelihood of developing psoriasis are identical in all patients and therefore family studies where the proband does not carry the particular psoriasis associated B-alleles are equally illuminating as to the inheritance pattern of disease.
C3H/HeJ mice do not respond to the polyclonal B-cell activator lipopolysaccharide (LPS) from Escherichia coli; this was first described by Sultzer who observed that mice of this strain did not respond to an intraperitoneal (i.p.) injection of LPS as measured by the accumulation of leukocytes in the peritoneal cavity. Neither were C3H/HeJ mice as susceptible to LPS toxcitiy (1). It was later reported that LPS-induced mitogenesis (2,3), adjuvanticity (4), and the appearance of Ia antigens on B lymphocytes as induced by LPS, (5) was also absent in C3H/HeJ mice. However, lymphocytes from these mice respond normally to the polyclonal B-cell activators purified protein derivative of tuberculin (2,6) and dextran sulfate and have also been reported to respond normally to concanavalin A (Con A) (2). Furthermore, the immune responses to sheep erythrocytes (7) and soluble thymus-dependent antigens (4) are normal in C3H/HeJ mice. Unresponsiveness to LPS in C3H/HeJ mice has been found to Be due to a defect in a single gene or a set of linked genes (3,8) which has been mapped between the major urinary protein locus and the locus coding for polysyndactyly on chromosome 4. (1) We have reported that injection of LPS into mice of an LPS-responsive strain causes a shift in the Con A dose-response curve of cultured spleen cells, suppressing the low does response (9). Therefore, we tested the Con A proliferative response in cultures of normal or LPS-activated spleen cells from LPS-responder (C3H/Tif) and LPS-nonresponder (C3H/HeJ) mice. We report here that C3H/HeJ spleen cells respond poorly to low concentrations of Con A (0.05-0.1 mug/ml). Injection of LPS 2 days before culture inhibits the response to low doses of Con A in cultures of C3H/Tif spleen cells but has no inhibitory effect on the dose response profile of C3H/HeJ spleen cells. Furthermore, the low dose Con A response of spleen cells is dependent upon the presence of an Ia-positive cell. (2) The role of Ia-positive cells in the Con A response of C3H/Tif and C3H/HeJ spleen cells is described.
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