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Cross-reactivity with mouse antigens in the ferritin immunogenetic (IR-gene) system.

Structural similarity between antigens and self molecules could be responsible for low antibody responses in different immunogenetic (IR-gene) systems. B10.M and B10.D2 strains are high responders, whilst A. Thy-1-1 mice are low responders, following primary immunization with ferritin in saline. Cross-reactivity between mouse-self antigens and ferritin was tested by antigen excess and radioimmunoassay techniques, using cells obtained from normal, unimmunized high- and low-responder mice, to compete for specific antibody. Low-responder A.Thy-1-1 mouse cells consistently displaced more anti-ferritin antibodies than did high-responder B10.M and B10.D2 mouse cells at varying antibody and cell concentrations and these differences were statistically significant (P less than 0.001). It is suggested that the responder status of different strains of mice, following primary immunization with ferritin in saline, could be explained by the degree of cross-activity between self determinants and antigen, such that low responders cross-react to a greater degree with the test antigen than do high-responder mice. A similar mechanism of cross-reactivity could operate in the pathogenesis of HLA-linked diseases.

Animals

HLA and other immunogenetic approaches to the study of diseases in man.

We have attempted to focus on several areas that can be practically explored to elucidate the mechanisms accounting for the polymorphism of the human major histocompatibility complex and attendent disease predispositions. In addition to widespread serologic HLA typing of specific populations, diseases, and families, it is important to improve discriminating methods for expoloration of other areas of the HLA supergene, especially those involved in specific immune responsiveness. It may also be necessary to take into account possible modulating effects of the MHC on other recognized human genes. Application of these improved methods to the study of infertile couples, recognized genetic syndromes, and human malignancies may assist in unraveling the immunogenetic enigma of these diseases.

Allergy and Immunology

An immunogenetic basis for the tissue involvement in Behçet's syndrome.

The multifocal involvement in Behçet's syndrome was grouped into a spectrum of four types, three of which appeared to have an immunogenetic basis. HLA-B5 was related to the ocular type of Behçet's syndrome (relative risk 7.3), HLA-B27 to the arthritic type (relative risk 12.1) and HLA-B12 to the muco-cutaneous type (relative risk 3.9). The concept that recurrent oral ulceration and Behçet's syndrome may belong to a disease spectrum is substantiated by the natural course of the disease. Furthermore, patients with recurrent oral ulcers share with the muco-cutaneous type of Behçet's syndrome a significantly increased frequency of HLA-B12 (relative risk 2.6). The HLA markers may also prove to be significant in the differential diagnosis and prognosis of a disease which may present under a confusing variety of clinical manifestations.

Adolescent

Suppression of antibody responses in allogeneic mice by products of lymphoid tissue. II. Lack of antigenic specificity and immunogenetic requirements of allogeneic suppressive factor (ASF).

Mice were irradiated, infused with thymocytes and immunized with a variety of antigens, i.e., sheep or horse red blood cells (SRBC or HRBC), diphtheria toxoid (DT) or bovine gamma-globulin (BGG). The spleen cells (T.Spleen cells) were harvested 5 days later and cellfree extracts were prepared. The extracts contained an allogeneic suppressive factor (ASF) that was capable of inhibiting IgM antibody responses of allogeneic or semi-allogeneic unirradiated mice. ASF had to be injected within 24 hr of immunization to be effective and a single injection delayed, rather than abolished, the antibody response at the cellular level. However, daily injections of ASF resulted in persistent suppression of antibody response. ASF activity was antigen nonspecific, i.e., the antigen used to stimulate ASF production did not have to be the same as the antigen used to test for ASF activity. C3H T.Spleen extracts were even immunosuppressive when prepared by exposure to C3BF1 alloantigens only; such extracts suppressed antibody responses of C3BF1 and DBA/2 mice. C3H ASF was removed from extracts after incubation with C3BF1 spleen cells but not after incubation with C3H spleen cells. C3BF1 spleen cells which had been preincubated with C3H ASF were unable to generate antibody-forming cells upon transfer to irradiated C3BF1 host mice. This suggests that the ASF molecule may be or include receptors for alloantigens. The immunogenetic requirements for ASF activity were evaluated by injecting extracts from C3H, C57BL, C3BF and BALB/c T.Spleen cells into C3H, CBA, C57BL, BALB/c, DBA/2, A or C3H.A recipient mice. All extracts tested had ASF activity. However, all allogeneic recipients were not suppressed by the extract material. The suppressive activity of ASF seemed to require two (or more) antigenic differences between donors and recipients of extract material, an H-2K or I antigen difference and a second antigen difference, possibility Ig-1. In the limited numbers of strain combinations tested, T.Spleen extracts suppressed IgM antibody response only if exposed to H-2 and Ig-1 antigens, e.g., BALB/c (H-2d, Ig-1a) ASF suppressed A (H-2a, Ig-1e) but not C3H.A (H-2a, Ig-1a) or DBA/2 (H-2d, Ig-1c). Separate ASF molecules may react with separate antigens on the cell surface, i.e., with H-2 and gammaG2a. Alternatively, one ASF molecule may react with two structurally associated antigens. If the latter is correct, it is conceivable that the beta2-microglobulin which is non-covalently linked to the major component of H-2 molecules expresses allotypic antigens coded for by Ig-1 and beta2-microglobulin is one of the antigens recognized by ASF.

Animals

[Immunogenetic analysis of the localization of the Y-factor in the mouse genome. I. Study of interspecific F1 hybrids].

Immunogenetic analysis of Y-factor localization in mouse genome was carried out by means of skin grafts. The data obtained indicate to autosomal localization of Y-factor rather than Y-linked one. This leads to the conclusion that Y-factor is a sex-influenced factor, but not a sex-linked one. If the hypothesis about Y-factor localization in Y-chromosome is accepted, this gene will be identical in CGA and C57B1/6 strains and the variety of reactions, caused by T-antigen, will be determined by the genetical constitution of the male donors and the female recipients.

Animals

Immunogenetic aspects of allotransplantation.

It now appears unequivocal that three markers exist in a linkage group in chromosome 6 of man: HLA-A, HLA-B and PGM3 (Fig. 1.) Tentatively, two other HLA loci and one Ir gene have been mapped close to HLA-B. The probable map order is HLA-A - HLA-C - HLA-B - HLA-D - Ir. The biological functions of these loci are unknown. However, HLA-A, B and C are important in allograft rejection. Other closely linked loci (HDR, CML) appear to be important in the first events of the allograft rejection (first set) and in generation of killer cells. HLA-D might be important in cellular recognition and graft-versus-host reactions (matching at HLA-D decreases the incidence and severity of graft-versus-host disease), and the Ir genes in the defense against infections. HLA-B and HLA-D loci are important markers in studies of disease susceptibility. HLA-B locus antigens HLA-B27 and HLA-B8 are frequently associated with arthritic or autoimmune disorders. HLA-D determinants have been found in association with multiple sclerosis and C2 deficiency (HLA-DW2); juvenile diabetes and Addison's disease (HLA-DW3) and adult type of rheumatoid arthritis (HLA-DW4).

Alleles

Linkage group HL-A-MLC-BF (properdin factor B). The site of the Bf locus at the immunogenetic linkage group on chromosome 6.

Genetic linkage between the HL-A and Bf loci could be confirmed in 43 families with 168 offspring. In 4 families, 5 recombinants out of 82 informative meiotic divisions were observed (r = 6.1%). The localisation of the Bf marker system was studied in 3 families with crossovers between HL-A and MLC. From these data the following map order of human chromosome 6 can be proposed: HL-A (1st locus) -- HL-A (2nd locus)--MLC-Bf---PGM(3). The fact that important components of the classical and alternate pathway of complement activation are governed by genes closely linked with HL-A and MLC loci leads to the proposition to include the Bf system into the Major Histocompatibility Complex in man.

Chromosome Mapping

Towards a unified theory for immunogenetic systems. I. Probing the serologic field--a meta-serologic approach.

A serologic field (SEF) is produced by the in vitro studies of antibody-antigen interactions and usually includes serologic information processing (SIF). SIF can be regarded as the process whereby essentially "meaningless" raw data or experimental observables emanating from an input reality are structuralized and hence falsified into a "meaningful" pattern, Gestalt or output image. According to this "black box model", different "fact categories" (FC) can be identified in SEF. Traditional serology generally confounds its FC whereby fact category mistakes (FCM) are produced. Some FCM are structurally similar to the description of "mice" as four-letter animals or as a four-legged word--i.e. facts about "thing-properties" (animals, legs) are confounded with facts about "language-properties" (letters, words). In SEF, antibody and antigen molecules (thing-properties) are similarly endowed with "empty symbols" (language-properties). Due to such FCM, radically new meanings are assigned to experimental observables if the serologic language and/or theory is changed. The present meta-serologic approach consists of the design of a meta-serologic symbol language (SL-2) which includes the contemporary (simple-complex) conceptual framework (language and theory) as a limiting case. Consequently, some truly radical and revolutionary Gestalt switches will be generated when a specified SEF is mapped onto SL-2.

Antigen-Antibody Reactions

A lymphocyte immunogenetic system, Atri, associated with the ABO blood group and the ABH secretor system.

The antigen Atri can be detected on the lymphocytes of 5.19% of A, ABH secretor individuals. The Atri substance is present in the plasma of the same individuals and can be fixed on group O erythrocytes. It is also found in the saliva of 30 out of 32 A non-secretor individuals. Its existence in the saliva of A secretor individuals, however, cannot be proved due to the presence of both the A and Atri antigens. The A AND Atri antigens have been shown to be distinct on lymphocytes by capping and by blocking of the A sites. The fact that in several families the Atri antigen is not expressed by the parents shows that its expression on lymphocytes requires the intervention of at least one gene in addition to ABO and Se.

ABO Blood-Group System

Conceptual framework shifts in immunogenetics. I. A new look at cis AB antigens in the ABO system.

The so-called 'cis AB' blood group is accounted for by proposing that 'normal' anti-A and anti-B reagents are cross-reacting with partially overlapping reaction ranges. Hence, they are labelled anti-AX and anti-BX, respectively. Some consequences of a complex-simple model where 'cis AB' is accordingly produced by a simple (mono-factorial) antigen X (produced a simple gene X at the ABO-locus) are briefly explored.

ABO Blood-Group System

Conceptual framework shifts in immunogenetics. II. Some notes on the Ag system.

Two Caucasian population materials totalling 530 individuals and 3,180 typing results are analyzed with regard to various combinations of the Ag(x, y, a1, d, c, g) factors. Superficially, both materials appear well aligned to each other and the contemporary (simple-complex) framework. However, when the same set of data are structuralized within a new (complex-simple) framework, the typing results for 12 of 362 or 3.3% of the Swiss and no less than 19 of 168 or 11.3% of the English samples are not compatible with the new framework specifying that the various anti-Ag reagents can be arranged in two 'inclusion groups'--the anti-Ag (y greater than d greater than c) and the anti-Ag (g greater than a1 greater than x) series.

England

Immunogenetics of the Lennox-Gastaut syndrome: frequency of HL-A antigens and haplotypes in patients and first-degree relatives.

Twenty-two patients with the Lennox-Gastaut syndrome and their families were examined for HL-A antigens by the microlymphocytotoxicity test. The antigen HL-A7 belonging to the HL-A locus showed a significantly increased frequency (p less than 0.0005) both in parents and in patients. The same antigen showed a significantly altered segregation in patients but a normal one in healthy siblings. Another antigen of the second HL-A locus, HL-A12, did not display a normal segregation in our patients, in whom it was nearly not represented.

Epilepsy