Repertoire Of Immune Responses Research Articles

The role of Pimpla hypochondriaca venom in the suppression of pupal Noctuid host immunity

When pupae of the Tomato moth (Lacanobia oleracea L.) (Lepidoptera: Noctuidae) are injected with venom from the endoparasitoid wasp Pimpla hypochondriaca Retzius (Hymenoptcra: Ichneumonidae), they show an increased susceptibility to the fungal entomopathogen Metarhizium anisopliae Sorokin (Fungi Imperfecti: Deuteromycotina). This observation, coupled with the fact that wasp eggs are comparatively unlikely to be encapsulated when implanted into envenomated pupae, suggests that venom of P. hypochondriaca suppresses the cellular immune defense mechanisms of L. oleracea. Injection of host pupae with the venom of P. hypochondriaca has a rapid, adverse effect on the normal respiration pattern of L. oleracea. It is possible that severe disruption to host-metabolism may contribute to a general failure in the hosts' normal immune response repertoire.

MHC-Peptide Binding

Small peptides, 8-10 amino acids long, derived from degradation of cytoplasmic proteins by a proteasome-proteinase complex, are usually presented and recognized by CD8+ cytolytic T lymphocytes (CTLs) associated with major histocompatibility complex (MHC) class I molecules. Recently synthetic peptides were used for the in vitro induction of tumor-specific CTLs, offering another strategy in the study of the immune-response repertoire and providing a new tool in cancer vaccination and immunotherapy. Peptides derived from otherwise normal proteins, overexpressed in many tumors as products of the protooncogene, may represent a target for an immune response. This is the case of HER-2/neu gene (also known as ErbB-2), encoding a cysteine-rich glycoprotein transmembrane receptor with tyrosine kinase activity (gp185neu). Recent data, demonstrating that HLA-A2.1-related peptides are able to stimulate in vitro CD8+ lymphocytes, Prompted us to study the binding to HLA-A2.1 molecules of several gp185 synthetic peptides containing a cystein residue and to define the relevance of this amino acid residue in the reduced or oxidated form of the sulfhydryl group. We found that monomers and their homodimers, linked by a disulfide bridge, bind to HLA-A2.1 molecules with overlapping affinity. These results suggest that additional amino acids of the nonapeptide do not prevent the binding and the HLA refolding through chemical or sterical interactions. This might be of particular relevance for the in vivo processing of cysteine-rich proteins. Because ErbB-2 molecules, as tumor-differentiation antigens in melanoma, are cysteine-rich molecules, it may be relevant to evaluate the possible role of the cystine residues interacting with the T-cell receptor. The recognition of these heterodimers by CD8+ lymphocytes will require functional in vivo studies.

Recognition by a murine monoclonal antibody of a unique epitope specific for the human alloantigen HLA-B8

A cytotoxic murine monoclonal antibody recognizing a specific HLA alloantigen was produced from the spleen cells of a BALB/c immunized with partially purified class I glycoproteins from an HLA-A1,B8 homozygous b-lymphoblastoid cell line. The antibody, designated P8.1, was tested against cells from 521 unrelated donors. It reacted with each of the 83 donors known to be HLA-B8 positive and with no HLA-B8 negative donors (sensitivity, 100%; specificity, 100%). Immunoprecipitation with antibody P8.1 and polyacrylamide gel electrophoresis confirmed that the antigen recognized was a class I structure. Although most murine monoclonal anti-HLA antibodies previously described have recognized “public” or supertypic specificities, the identification of a monoclonal antibody specific for a “private” HLA alloantigen indicates first that the BALB/c mouse has the appropriate immune response repertoire for recognizing certain HLA allospecificities and second that HLA-B8 can be defined by a single unique epitope.

A SOLUTION TO THE GENETIC AND ENVIRONMENTAL PUZZLES OF INSULIN-DEPENDENT DIABETES MELLITUS

Studies of the segregation of heterozygous immunoglobulin allotypes in families with several cases of insulin-dependent diabetes mellitus (IDDM) show that germline heavy-chain V (variable region) genes are not major genetic determinants for IDDM, but data for IDDM and Graves' disease together suggest involvement of xlight-chain V genes. Absence of IDDM at birth, the semi-random age of onset, and the 50% discordance of identical twins suggest that somatic mutation of germline V genes is involved in the development of the pathogenetic anti-beta-cell clones. The effect of histocompatibility and other alloantigens on the prevalence of IDDM is readily accounted for by the effect of the "holes" they induce, by natural tolerance, in the immune response repertoire; these alterations apparently affect the chance of emergence of anti-beta-cell clones by the somatic mutations and network of interclonal deletions that constantly change the fringes of the repertoire. Histocompatibility antigens can also influence repertoire development by changing the specificity of conjoint presentation of foreign antigens by macrophages. Antigenic stimulation by particular environmental microorganisms is probably essential to the repertoire development necessary for the occurrence of IDDM. Additionally, beta-cell damage by local infection may play a part by facilitating autoantigen presentation to the immune system.

On the nature of the genes influencing the prevalence of Graves' disease

Burnet's theory that Graves' and other autoimmune diseases are caused by forbidden clones of immunocytes, reactive against host antigens and emerging in post-natal life due to somatic events (somatic mutations of V genes and inter-clonal deletions), remains the most comprehensive and likely concept of the pathogenesis. The MHC antigens, B8 and D/DR3, have a predisposing influence of × 2.5 and × 3.7 respectively, whilst male sex has a protective influence, ÷ 6. Family studies testing for associated inheritance of Graves' disease and immunoglobulin allotypes (Gm and Km), by observation of the segregation of known heterzygous allotypes and also by Penrose's sibling pair method, have failed to show involvement of immunoglobulin genes. The H gene theory , prompted by studies on the inheritance of autoimmune diseases in the New Zealand mice, postulates that germline genes influencing the prevalence of Graves' and other autoimmune diseases code for major and minor histocompatibility or other alloantigens. By deleting complementary clones, alloantigens alter the immune response repertoire of each individual and this could alter the chance of emergence of a forbidden clone by the somatic mutations and the inter-clonal deletions envisaged by Burnet and Jerne. The H gene theory is superior to the linkage disequilibrium theory in that it accounts for all the known genetic features of Graves' disease, including the female sex preponderance, which is ascribed to the effect of clonal deletions imposed by the H-Y antigen.

The genetic basis of autoimmune disease.

The genetic predisposition to autoimmune disease in man is largely specific for each disease, indicating that these diseases are based not on a generalized breakdown of a tolerance mechanism, but on highly specific abnormalities of immune responsiveness which are subject to genetic transmission. In the presence of particular antigens encoded in the major histocompatibility complex (MHC) the relative risk of certain autoimmune diseases is increased, or in some cases decreased, and the increased risk has been widely attributed to linkage disequilibrium with unidentified disease-causing genes. Our studies on the inheritance of spontaneous autoimmune diseases in New Zealand mice have revealed that small numbers of dominant genes, some associated with the MHC but the remainder elsewhere in the genome, determine susceptibility to these diseases. That MHC-linked genes are not of paramount importance casts doubt on the linkage disequilibrium hypothesis. An alternative possibility is that major and minor histocompatibility antigens themselves predispose to the development of autoimmune diseases by altering the immune response repertoire through the effect of their clonal deletions on the network of paratope-idiotope clonal interactions. Such alterations could influence the chances of emergence, by somatic mutation, of pathogenic forbidden clones.