Specific Immune Response Genes Research Articles

Ten-eleven translocation 2 modulates allergic inflammation by 5-hydroxymethylcytosine remodeling of immunologic pathways.

Allergic rhinitis (AR) is an allergen-specific immunoglobulin E-mediated inflammatory disease. Both genetic and environmental factors could play a role in the pathophysiology of AR. 5-methylcytosine (5mC) can be converted to 5-hydroxymethylcytosine (5hmC) by the ten-eleven translocation (Tet) family of proteins as part of active deoxyribonucleic acid (DNA) demethylation pathway. 5hmC plays an important role in the regulation of gene expression and differentiation in immune cells. Here, we show that loss of Tet protein 2 (Tet2) could impact the severity of AR in the ovalbumin-induced mouse model. Genome-wide 5hmC profiling of both wild-type and Tet2 KO mice in response to AR revealed that the loss of Tet2 could lead to 5hmC alteration at specific immune response genes. Both partial loss and complete loss of Tet2 alters the 5hmC dynamic remodeling for the adaptive immune pathway as well as cytokines. Thus, our results reveal a new role of Tet2 in immunology, and Tet2 may serve as a promising target in regulating the level of immune response.

Immune Differentiation Regulator p100 Tunes NF-κB Responses to TNF.

Tumor necrosis factor (TNF) is a pleiotropic cytokine whose primary physiological function involves coordinating inflammatory and adaptive immune responses. However, uncontrolled TNF signaling causes aberrant inflammation and has been implicated in several human ailments. Therefore, an understanding of the molecular mechanisms underlying dynamical and gene controls of TNF signaling bear significance for human health. As such, TNF engages the canonical nuclear factor kappa B (NF-κB) pathway to activate RelA:p50 heterodimers, which induce expression of specific immune response genes. Brief and chronic TNF stimulation produces transient and long-lasting NF-κB activities, respectively. Negative feedback regulators of the canonical pathway, including IκBα, are thought to ensure transient RelA:p50 responses to short-lived TNF signals. The non-canonical NF-κB pathway mediates RelB activity during immune differentiation involving p100. We uncovered an unexpected role of p100 in TNF signaling. Brief TNF stimulation of p100-deficient cells triggered an additional late NF-κB activity consisting of RelB:p50 heterodimers, which modified the TNF-induced gene-expression program. In p100-deficient cells subjected to brief TNF stimulation, RelB:p50 not only sustained the expression of a subset of RelA-target immune response genes but also activated additional genes that were not normally induced by TNF in WT mouse embryonic fibroblasts (MEFs) and were related to immune differentiation and metabolic processes. Despite this RelB-mediated distinct gene control, however, RelA and RelB bound to mostly overlapping chromatin sites in p100-deficient cells. Repeated TNF pulses strengthened this RelB:p50 activity, which was supported by NF-κB-driven RelB synthesis. Finally, brief TNF stimulation elicited late-acting expressions of NF-κB target pro-survival genes in p100-deficient myeloma cells. In sum, our study suggests that the immune-differentiation regulator p100 enforces specificity of TNF signaling and that varied p100 levels may provide for modifying TNF responses in diverse physiological and pathological settings.

Neuroepithelial control of mucosal inflammation in acute cystitis

The nervous system is engaged by infection, indirectly through inflammatory cascades or directly, by bacterial attack on nerve cells. Here we identify a neuro-epithelial activation loop that participates in the control of mucosal inflammation and pain in acute cystitis. We show that infection activates Neurokinin-1 receptor (NK1R) and Substance P (SP) expression in nerve cells and bladder epithelial cells in vitro and in vivo in the urinary bladder mucosa. Specific innate immune response genes regulated this mucosal response, and single gene deletions resulted either in protection (Tlr4−/− and Il1b−/− mice) or in accentuated bladder pathology (Asc−/− and Nlrp3−/− mice), compared to controls. NK1R/SP expression was lower in Tlr4−/− and Il1b−/− mice than in C56BL/6WT controls but in Asc−/− and Nlrp3−/− mice, NK1R over-activation accompanied the exaggerated disease phenotype, due, in part to transcriptional de-repression of Tacr1. Pharmacologic NK1R inhibitors attenuated acute cystitis in susceptible mice, supporting a role in disease pathogenesis. Clinical relevance was suggested by elevated urine SP levels in patients with acute cystitis, compared to patients with asymptomatic bacteriuria identifying NK1R/SP as potential therapeutic targets. We propose that NK1R and SP influence the severity of acute cystitis through a neuro-epithelial activation loop that controls pain and mucosal inflammation.

Microarray analysis of human keratinocytes from different anatomic sites reveals site-specific immune signaling and responses to human papillomavirus type 16 transfection

BackgroundStratified human keratinocytes (SHKs) are an essential part of mucosal innate immune response that modulates adaptive immunity to microbes encountered in the environment. The importance of these SHKs in mucosal integrity and development has been well characterized, however their regulatory immunologic role at different mucosal sites, has not. In this study we compared the immune gene expression of SHKs from five different anatomical sites before and after HPV16 transfection using microarray analyses.MethodsIndividual pools of human keratinocytes from foreskin, cervix, vagina, gingiva, and tonsils (HFKs, HCKs, HVKs, HGKs and HTLKs) were prepared. Organotypic (raft) cultures were established for both normal and HPV16 immortalized HFKs, HCKs, HVKs, HGKs and HTLKs lines which stably maintained episomal HPV16 DNA. Microarray analysis was carried out using the HumanHT-12 V4 gene chip (Illumina). Immune gene expression profiles were obtained by global gene chip (GeneSifter) and Ingenuity pathway analysis (IPA) for each individual site, with or without HPV16 transfection.ResultsWe examined site specific innate immune response gene expression in SHKs from all five different anatomical sites before and after HPV16 transfection. We observed marked differences in SHK immune gene repertoires within and between mucosal tracts before HPV 16 infection. In addition, we observed additional changes in SHKs immune gene repertoire patterns when these SHKs were productively transfected with HPV16. Some immune response genes were similarly expressed by SHKs from different sites. However, there was also variable expression of non-immune response genes, such as keratin genes, by the different SHKs.ConclusionsOur results suggest that keratinocytes from different anatomical sites are likely hard wired in their innate immune responses, and that these immune responses are unique depending on the anatomical site from which the SHKs were derived. These observations may help explain why select HPV types predominate at different mucosal sites, cause persistent infection at these sites, and on occasion, lead to HPV induced malignant and benign tumor development.

Analysis of immune-related genes during Nora virus infection of Drosophila melanogaster using next generation sequencing.

Drosophila melanogaster depends upon the innate immune system to regulate and combat viral infection. This is a complex, yet widely conserved process that involves a number of immune pathways and gene interactions. In addition, expression of genes involved in immunity are differentially regulated as the organism ages. This is particularly true for viruses that demonstrate chronic infection, as is seen with Nora virus. Nora virus is a persistent non-pathogenic virus that replicates in a horizontal manner in D. melanogaster. The genes involved in the regulation of the immune response to Nora virus infection are largely unknown. In addition, the temporal response of immune response genes as a result of infection has not been examined. In this study, D. melanogaster either infected with Nora virus or left uninfected were aged for 2, 10, 20 and 30 days. The RNA from these samples was analyzed by next generation sequencing (NGS) and the resulting immune-related genes evaluated by utilizing both the PANTHER and DAVID databases, as well as comparison to lists of immune related genes and FlyBase. The data demonstrate that Nora virus infected D. melanogaster exhibit an increase in immune related gene expression over time. In addition, at day 30, the data demonstrate that a persistent immune response may occur leading to an upregulation of specific immune response genes. These results demonstrate the utility of NGS in determining the potential immune system genes involved in Nora virus replication, chronic infection and involvement of antiviral pathways.

Correlative Gene Expression to Protective Seroconversion in Rift Valley Fever Vaccinates.

Rift Valley fever Virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease, Rift Valley fever (RVF). In both humans and livestock, protective immunity can be achieved through vaccination. Earlier and more recent vaccine trials in cattle and sheep demonstrated a strong neutralizing antibody and total IgG response induced by the RVF vaccine, authentic recombinant MP-12 (arMP-12). From previous work, protective immunity in sheep and cattle vaccinates normally occurs from 7 to 21 days after inoculation with arMP-12. While the serology and protective response induced by arMP-12 has been studied, little attention has been paid to the underlying molecular and genetic events occurring prior to the serologic immune response. To address this, we isolated RNA from whole blood of vaccinated calves over a time course of 21 days before and after vaccination with arMP-12. The time course RNAs were sequenced by RNASeq and bioinformatically analyzed. Our results revealed time-dependent activation or repression of numerous gene ontologies and pathways related to the vaccine induced immune response and its regulation. Additional bioinformatic analyses identified a correlative relationship between specific host immune response genes and protective immunity prior to the detection of protective serum neutralizing antibody responses. These results contribute an important proof of concept for identifying molecular and genetic components underlying the immune response to RVF vaccination and protection prior to serologic detection.

Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent TFH–B cell axis

Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (T(FH)), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6(pos) B cells were located at the vicinity of cells expressing the programmed death 1 (PD-1) T(FH) marker. Moreover, purified FL-derived T(FH), expressed IL4 at very high levels compared with purified tonsil-derived T(FH) or non-T(FH) microenvironment. Altogether, our study demonstrated that tumor-infiltrating T(FH) specifically express functional IL-4 in FL, creating an IL-4-dependent T(FH)-B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target.

Follicular Lymphoma Cell Niche: Identification of a Preeminent IL-4-Dependent TFH- B Cell Axis.

Abstract 757Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained on whole biopsy samples, have been associated with patient survival, independently of classical clinical features. In this study we performed, using Affymetrix U133 Plus 2.0 oligonucleotide microarrays, the gene expression profiling of purified CD19pos B-cell and CD19negCD22neg non-B cell compartments, prospectively obtained from FL and reactive lymph nodes. Unsupervised analyses of B-cell compartment in one hand (n=21) and non-B cell compartment in the other hand (n=14) allowed to differentiate FL from reactive samples. We then identified 677 nonredundant genes defining the FL synapse, i.e. the list of genes involved in the crosstalk between B cells and their microenvironment in FL. Using Ingenuity pathway analysis we pointed out 26 FL-specific functional networks among this FL synapse, including an IL-4-centered pathway. Interestingly, whereas in tonsils and reactive lymph nodes only exceptional scattered phospho-STAT6pos cells were observed, a high number of CD20posphospho-STAT6pos cells were evidenced within FL biopsies. In addition, several IL-4-target genes, including IL4I1 and HOXC4, were overexpressed in malignant B cells. Altogether, these results demonstrated that the upregulation of IL-4 within FL microenvironment was associated to a strong activation of FL B cells. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (TFH), as demonstrated through both Gene Set Enrichment Analysis (GSEA)-based transcriptomic approach and flow cytometry analysis of the CD4posCXCR5hiICOShi cell compartment. The majority of phospho-STAT6pos B cells were located at the vicinity of cells expressing the PD-1 TFH marker. Moreover, purified FL-derived TFH, unlike non-TFH T cells, expressed IL4. Finally, whereas chronically inflamed tonsils also exhibited an increase percentage of TFH cells, tonsil-derived TFH did not express IL4. Altogether, our study demonstrated that tumor-infiltrating TFH specifically express functional IL-4 in FL, creating therefore an IL-4-dependent TFH-B cell axis. This crosstalk could sustain FL pathogenesis and represent a new potential therapeutic target. Disclosures:No relevant conflicts of interest to declare.

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP beta chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) beta(1) genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-beta(1) (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (-308) PM. The most significant results were found for the TGF-beta(1) (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-beta(1) (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-beta(1) (codon 25) PM genotype frequency associated with a low TGF-beta release suggests that immunoregulatory cytokines such as TGF-beta are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF-alpha and TGF-beta(1), with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.

Factors governing the human immune response to injected insulin.

Seventy-nine patients were observed prospectively during their initial period of treatment with conventional bovine insulins. Insulin antibody levels 6 months after starting insulin therapy did not correlate with age, gender or beta cell function at onset of treatment. Patients who required soluble insulin in addition to isophane insulin developed higher levels of insulin antibody. Patients bearing the HLA-B8, DR3 and C4AQO alleles had lower levels of insulin antibody, whereas those bearing DR7 produced significantly higher levels. Other alleles at the C4A, C4B, C2, factor B or Gm loci did not appear to have a significant effect on insulin antibody production. The hyporesponsiveness of B8/DR3/ C4AQO -positive individuals probably reflects a non-specific abnormality of immunity whereas the enhanced responsiveness of those positive for DR7 suggests the presence of a specific immune response gene for insulin.

Antibodies to SS-B in chronic inflammatory connective tissue diseases. Relationship with HLA-Dw2 and HLA-Dw3 antigens in primary Sjögren's syndrome.

SS-B antigen, purified from rabbit thymus, was used in an indirect enzyme immunoassay to demonstrate the presence of IgG-, IgA-, and IgM-type SS-B antibodies in sera from patients with well-defined and characterized chronic inflammatory connective tissue disease. High levels of antibodies to SS-B were found in patients with primary and secondary Sjögren's syndrome. Patients with Sjögren's syndrome secondary to systemic lupus erythematosus had significantly higher SS-B antibody values than patients with Sjögren's syndrome secondary to rheumatoid arthritis or patients with rheumatoid arthritis or systemic lupus erythematosus, alone. Two patients with rheumatoid arthritis without secondary Sjögren's syndrome also had a markedly elevated level of antibodies to SS-B. Antibodies of all immunoglobulin classes were found, although the highest values were either IgG- or IgM-type. In primary Sjögren's syndrome, antibody values to SS-B were higher in patients with HLA-Dw2 and/or HLA Dw3 than in those with other HLA-Dw types. We conclude that these antigens or specific immune-response genes close to the D region may be important for the development of antibodies to SS-B.

The role of H-2 I region genes in regulation of the immune response.

The evidence of the past 10 years indicates that genes mapping in the I region of the mouse major histocompatibility complex (H-2) regulate a bewildering array of immunologic functions. A survey of H-2-linked specific immune response (Ir) genes shows that the phenotypic effect of these genes is to enable a particular inbred strain to discriminate and recognize remarkably precise chemical specificities, such as one or two amino acid interchanges in a polypeptide chain. The only I region gene products which have been identified to date are the Ia antigens. These include five readily detectable polypeptide chains (Aa, Ab, Ae, Ea, and Ii) and several other serologically distinct entities which are selectively expressed on functionally distinct T cell subsets (J1, J2?, J3? and C). The specificity of recognition of Ir genes would seem to require a larger number of I region gene products than can be generated even by combinatorial association of the four readily identifiable peptides (to give eight combinatorial associations) and the other serologically identified gene products. If the Ia antigens are to function as an antigen specific receptor system, separate from immunoglobulin molecules, there must be other, as yet undetected, I region gene products (e.g. Ia antigens). Alternatively, the known I region gene products could function by any one of several postulated mechanisms to generate an antigen specific T cell receptor system. The available evidence for the total number of I region gene products is reviewed, and the alternate possibilities are briefly discussed in this presentation.

Serologic subsets in systemic lupus erythematosus: an examination of autoantibodies in relationship to clinical features of disease and HLA antigens.

A search for anti-Ro or anti-nRNP antibodies by precipitin analysis among a population of 64 patients with systemic lupus erythematosus (SLE) or mixed connective tissue disease was undertaken. The 25% of SLE patients with anti-Ro did not have any distinct clinical features, compared to patients without anti-Ro or to anti-nRNP patients with SLE or mixed connective tissue disease. However, these patients did have a significantly greater frequency of rheumatoid factor (80%). Most importantly however, patients with anti-Ro had a significantly increased frequency of HLA-B8 (81%) and HLA-DRw3 (100%) compared to patients with anti-nRNP (B8--29%; DRw3--33%) or SLE patients without such antibodies (B8--41%; DRw3--25%). These data suggest the existence of a specific immune response gene for Ro close to the D region of the major histocompatibility complex.

Polyarthritis: The differential diagnosis of rheumatoid arthritis

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects many organ systems, is more prevalent in females, and has no known etiology. Moreover, the presentation of patients with the disease can be as diverse as the many systems in the body that it can affect. The systems commonly involved include muscle and joints, brain and peripheral nervous system, lungs, heart, kidneys, skin, serous membranes, and components of the blood. This disease is complex and often affects one organ system to the exclusion of others. Moreover, the clinical manifestations are protean, overlap with other illnesses, and are often subtle. The complex nature of lupus could explain the convergence of seemingly unrelated abnormalities and the varied nature of pathology observed from patient to patient in this illness. Although lupus is largely associated with specific immune response genes in the MHC class II or class III regions, there are new and exciting genetic associations that include other loci. Suspected pathogenetic factors, such as sex steroid hormones or gonadotrophins such as prolactin, may play a role in the severity of the disease and the different clinical presentations. Environmental factors such as drugs, diet, and toxins have also been implicated in the pathogenesis of SLE. Immunological tests, which are specific to most autoimmune diseases such as lupus, include the presence of specific cytotoxic lymphocytes and a variety of autoantibodies, including a persistently positive antinuclear antibody. Although there are a few nonimmunologic laboratory characteristics of SLE, these are not specific.

Opinion

Abstract Ever since the discovery of specific immune response (Ir) genes in the I regions of the major histocompatibility complex (MHC) of mammals (1), certain characteristic features of the phenomena they control presented a considerable challenge: H-linked Ir gene control has been observed only for thymus-dependent antigens that are proteins or polypeptides, and is concerned with T cell responses such as the stimulation of delayed-type hypersensitivity (DTH) and specific helper T cells (1, 2).The specificity of Ir gene function is remarkable and distinguishes readily between antigens with different amino acid primary sequences (3–6). This has been demonstrated for synthetic antigens and also for native antigens. It is nevertheless remarkably distinct from the specificity of the T cell responses themselves (7), a matter of considerable concern to me when we initially proposed that the Ir gene product could be the elusive T cell receptor (1).

Genetic aspects of immunologic abnormalities in New Zealand mouse strains

Since preliminary evidence indicated that a gene locus associated with the chocolate coat color had an inhibitory effect on the spontaneous development of autoimmune hemolytic anemia–which in turn was associated with a dominant gene–we accordingly initiated the development of a congenic line of NZB mice carrying the chocolate coat color locus (and other genes closely linked to this locus). After eight backcross generations to NZB, an inbred line of mice carrying the chocolate coat color gene was established and then studied for incidence of anti-RBC autoantibodies. The congenic line NZB.ch shows a considerably lower incidence of such autoantibodies, particularly in male mice. Although further analysis is still required, we propose that the genetic control of autoimmunity is based on the resultant interaction of several gene loci: 1) a single dominant locus (A) that predisposes to an autoimmune state rather than the maintenance of (self) tolerance, 2) a modifying locus (M) linked to ch., subject to gene dosage, which particularly in the recessive state can inhibit the effect of the A locus, and 3) a cluster of specific immune response genes that are associated with specific autoantibody responses, e.g. antinucleic acid antibodies, and are probably H2 linked. Our current analysis does not suggest that the A or M loci are linked to the MHC. It is also proposed that the wild-type allele of the M locus is carried by normal mouse strains, that NZB mice have a completely inactive allele at this locus, and that NZC mice have a third allele detectable only in the homozygous state.

Specific immune response genes of new inbred strains of guinea pigs.

Distribution of specific immune-response (Ir) genes controlling responsiveness to synthetic polypeptide antigens, homopolymer of poly-L-lysine (PLL), copolymer of L-glutamic acid and L-alanine (GA) and copolymer of L-glutamic acid and L-tyrosine (GT), and limiting doses of 2,4-dinitrophenyl guinea pig serum albumin (DNP-GPA) was surveyed in new inbred strains of guinea pigs, JY 1, JY 2, JY 9 and JY 10, established in this Institute. The PLL gene was not found in any of the guinea pigs. The GA gene was found in JY 1 and JY 2 guinea pigs and the GT gene in all the guinea pigs. The gene controlling responsiveness to low doses (1 microgram) of DNP-GPA was found in JY 1, JY 9 and JY 10 guinea pigs. The associated (Ia) antigens was discussed.

The nature and functions of specific immune response genes and their products.

Antibodies produced by inbred mouse strains immunized with the random synthetic polypeptide poly (Tyr,Glu)-poly(DLAla)--polyLys denoted (T,G)-A--L were found to be specific mainly to the ordered peptide Tyr-Tyr-Glu-Glu. Low responder H-2k mice, upon immunization with either the random (T,G)-A--L or the ordered (T-T-G-G)-A--L coupled to methylated bovine serum albumin (MBSA), produce antibodies with comparable titers to those observed in high responder H-2b mice following immunization with the antigens alone or with their complexes with MBSA. A comparison of the above antibodies have led to the conclusion that low responder mice, upon immunization with the synthetic antigens complexed with MBSA, produce antibodies of the same specificity and quality as those of high responders (as shown by the isoelectric focusing technique) and they also have the same affinity and heterogeneity as antibodies of H-2b mice (measured by equilibrium dialysis and antigen binding capacity assay). Anti-idiotypic sera to anti-T,G)-A--L antibodies of C3H.SW (H-2b,Ig-1a) mice were raised in guinea pigs. C3H.SW anti-(T,G)-A--L antibodies from different pools cross reacted idiotypically. Anti-(T,G)-A--L antibodies of CWB (H-2b, Ig-1b) mice did not react with the anti-idiotypic serum suggesting linkage between the genes coding for idiotypes and allotypes. C3H/DiSn (H-2k, Ig-1a) anti-(T,G)-A--L antibodies elicited by immunization with (T,G)-A--L complexed to MBSA reacted with the anti-idiotypic serum to the same degree as C3H.SW anti-(T,G)-A--L antibodies, confirming the similarity between the high and low responder anti-(T,G)-A--L antibodies. C3H.SW (H-2b) mice as well as C3H/DiSn (H-2k) mice were found to be capable of producing an antigen specific factor from "educated" T cells which replaces the helper effect of T cells in the process of antibody production. On the other hand B cells of H-2k mice were not triggered by a factor of either high or low responder specific T cells. The activity of a C3H.SW (T,G)-A--L specific T cell factor was removed after passage on a Sepharose column coupled to the anti-idiotypic serum prepared against C3H.SW anti-(T,G)-A--L antibodies, suggesting similarity between the antigen specific T cell factor and the B cell recognition system. A (T,G)-A--L specific factor produced by C3H/DiSn (H-2k, Ig-1a) "educated" T cells reacted with the anti-idiotypic serum as well. Thus, C3H.SW high and C3H/DiSn low responder (T,G)-A--L specific T cell factors cross react at the level of their binding site for antigen.

B lymphocyte alloantigens controlled by theI region of the major histocompatibility complex in mice

An antiserum was produced by reciprocal immunization of congenic resistent inbred strains of mice which differed only with respect to theI andS regions of theH- 2 complex. This antiserum permitted the serological detection of lymphocyte alloantigens, designated Ia (=I region associated antigens). Ia determinants are only present on mature B lymphocytes. They could not be found on thymocytes, splenic or lymph node T cells, or on the majority of bone marrow cells. Absorption studies demonstrated existence of several Ia specificities which are associated with differentI region types. Thus, theI region of theH- 2 complex appears to control not only T-cellexpressed antigen specific immune response genes, but also B-cell-expressed Ia determinants. The relevance of the Ia alloantigen system for cellular interaction in immune reactions is discussed.

Kidney transplantation between congenic versus standard inbred strains of rats: I The significance ofH-1 and non-H-1 gene differences

Concepts of “antigenic strength” in organ transplantation have been evaluated in relation to orthotopic kidney allografts inH-1 congenic strains of rats. Untreated recipients reject fully allogeneic kidneys possessing singleH-1 differences as acutely as kidneys displaying multiple histocompatibility differences. Heterozygozity for H-1 specificities as well as for H-1 plus non-H-1 specificities (semiallogeneic kidneys) favors long term survival (autoenhancement), especially when the specific immune response genes of the recipient lead to reduced reactivity. In active enhancement, the transplantedH-1 congenic kidneys, devoid of additional weak antigens, retain prolonged functional integrity. Weak non-H-1 antigens substantially influence the successful establishment of specific enhancement in an adverse way, either as additive immunogens or as target sites for the effector arm of the rejection response.