scholarly journals EVOLUTION OF THE IMMUNE RESPONSE

1964 ◽  
Vol 119 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Ben W. Papermaster ◽  
Richard M. Condie ◽  
Joanne Finstad ◽  
Robert A. Good
Keyword(s):  
Adaptive Immunity ◽  
Primary Response ◽  
Antigenic Stimulation ◽  
Secondary Response ◽  
Immunologic Reactivity ◽  
Starch Gel ◽  
Eptatretus Stoutii ◽  
Amia Calva ◽  
Secondary Stimulation ◽  
Bacteriophage T2

1. The California hagfish, Eptatretus stoutii, seems to be completely lacking in adaptive immunity: it forms no detectable circulating antibody despite intensive stimulation with a range of antigens; it does not show reactivity to old tuberculin following sensitization with BCG; and gives no evidence of homograft immunity. 2. Studies on the sea lamprey, Petromyzon marinus, have been limited to the response to bacteriophage T2 and hemocyanin in small groups of spawning animals. They suggest that the lamprey may have a low degree of immunologic reactivity. 3. One holostean, the bowfin (Amia calva) and the guitarfish (Rhinobatos productus), an elasmobranch, showed a low level of primary response to phage and hemocyanin. The response is slow and antibody levels low. Both the bowfin and the guitarfish showed a vigorous secondary response to phage, but neither showed much enhancement of reactivity to hemocyanin in the secondary response. The bowfin formed precipitating antibody to hemocyanin, but the guitarfish did not. Both hemagglutinating and precipitating antibody to hemocyanin were also observed in the primary response of the black bass. 4. The bowfin was successfully sensitized to Ascaris antigen, and lesions of the delayed type developed after challenge at varying intervals following sensitization. 5. The horned shark (Heterodontus franciscii) regularly cleared hemocyanin from the circulation after both primary and secondary antigenic stimulation, and regularly formed hemagglutinating antibody, but not precipitating antibody, after both primary and secondary stimulation with this antigen. These animals regularly cleared bacteriophage from the circulation after both the primary and secondary stimulation with bacteriophage T2. Significant but small amounts of antibody were produced in a few animals in the primary response, and larger amounts in the responding animals after secondary antigenic stimulation. 6. Studies by starch gel and immunoelectrophoresis show that the hagfish has no bands with mobilities of mammalian gamma globulins; that the lamprey has a single, relatively faint band of this type; and that multiple gamma bands are characteristic of the holostean, elasmobranchs, and teleosts studied. By this method of study, the bowfin appeared to have substantial amounts of gamma2 globulin. 7. We conclude that adaptive immunity and its cellular and humoral correlates developed in the lowest vertebrates, and that a rising level of immunologic reactivity and an increasingly differentiated and complex immunologic mechanism are observed going up the phylogenetic scale from the hagfish, to the lamprey, to the elasmobranchs, to the holosteans, and finally the teleosts.

scholarly journals POS0461 RESPONSE TO BIOLOGIC THERAPY IN RHEUMATOID ARTHRITIS: RETHINKING OUR CLASSIFICATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 462.1-462
Author(s):  
E. Vallejo-Yagüe ◽  
S. Kandhasamy ◽  
E. Keystone ◽  
A. Finckh ◽  
R. Micheroli ◽  
...  
Keyword(s):  
Treatment Response ◽  
Real World ◽  
Observational Studies ◽  
Initial Response ◽  
Primary Response ◽  
Sustained Response ◽  
Secondary Response ◽  
Real World Data ◽  
World Data ◽  
Secondary Failure

Background:In rheumatoid arthritis (RA), primary failure with biologic treatment may be understood as lack of initial clinical response, while secondary failure would be loss of effectiveness after an initial response. Despite these clinical concepts, there is no unifying operational definition of primary and secondary non-response to RA treatment in observational studies using real-world data. On top of data-driven challenges, when conceptualizing secondary non-responders, it is unclear if the mechanism behind loss of effectiveness after a brief initial response is similar to loss of effectiveness after previous benefit sustained over time.Objectives:This viewpoint aims to motivate discussion on how to define primary and secondary non-response in observational studies. Ultimately, we aim to trigger expert committees to develop standard terminology for these concepts.Methods:We discuss different methodologies for defining primary and secondary non-response in observational studies. To do so, we shortly overview challenges characteristic of performing observational studies in real-world data, and subsequently, we conceptualize whether treatment response should be a dichotomous classification (Primary response/non-response; Secondary response/non-response), or whether one should consider three response categories (Primary response/non-response; Primary sustained/non-sustained response; Secondary response/non-response).Results:RA or biologic registries are a common data source for studying treatment response in real-world data. While registries include disease-specific variables to assess disease progression, missing data, loss of follow-up, and visits restricted to the year or mid-year visit may present a challenge. We believe there is a general agreement to assess primary response within the first 6 month of treatment. However, conceptualizing secondary non-response, one could wonder if a patient with brief initial response and immediate loss of it should belong to the same response category as a patient who relapses after a period of prior benefit that was sustained over time. Until this concern is clarified, we recommend considering a period of sustained response as a pre-requisite for secondary failure. This would result in the following three categories: a) Primary non-response: Lack of response within the first 6 months of treatment; b) Primary sustained response: Maintenance of a positive effectiveness outcome for at least the first 12 months since treatment start; c) Secondary non-response: Loss of effectiveness after achieved primary sustained response. Figure 1 illustrates this classification through a decision tree. Since the underlying mechanisms for treatment failure may differ among the above-mentioned categories, we recommend to use the three-category classification. However, since this may pose additional methodological challenges in real-world data, optionally, a dichotomous 12-month time-point may be used to assess secondary non-response (unfavourable outcome after 12-months) in comparison to primary non-response or non-sustained response (unfavourable outcome within the first 12-months). Similarly, to study primary response, the solely 6-month timepoint may be used.Conclusion:A unified operational definition of treatment response will minimize heterogeneity among observational studies and help improve the ability to draw cross-study comparisons, which we believe would be of particular interest when identifying predictors of treatment failure. Thus, we hope to open the room for discussion and encourage expert committees to work towards a common approach to assess treatment primary and secondary non-response in RA in observational studies.Disclosure of Interests:Enriqueta Vallejo-Yagüe: None declared, Sreemanjari Kandhasamy: None declared, Edward Keystone Speakers bureau: Amgen, AbbVie, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Novartis, Pfizer Pharmaceuticals, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb Company, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, PuraPharm, Axel Finckh Speakers bureau: Pfizer, Eli-Lilly, Paid instructor for: Pfizer, Eli-Lilly, Consultant of: AbbVie, AB2Bio, BMS, Gilead, Pfizer, Viatris, Grant/research support from: Pfizer, BMS, Novartis, Raphael Micheroli Consultant of: Gilead, Eli-Lilly, Pfizer and Abbvie, Andrea Michelle Burden: None declared

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4273-4280 ◽  
Author(s):  
Su Jeong Ryu ◽  
Kyung Min Jung ◽  
Hyun Seung Yoo ◽  
Tae Woo Kim ◽  
Sol Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Primary Response ◽  
Hematopoietic Cell ◽  
Secondary Response ◽  
Memory Cd8 T Cells ◽  
Specific Memory ◽  
Cd4 Help ◽  
Different Response

AbstractIn contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell–specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.

Differential expression of Broad-Complex transcription factors may forecast tissue-specific developmental fates during Drosophila metamorphosis

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3275-3287 ◽  
Author(s):  
I.F. Emery ◽  
V. Bedian ◽  
G.M. Guild
Keyword(s):  
Western Blot ◽  
Expression Patterns ◽  
Primary Response ◽  
Protein Isoforms ◽  
Secondary Response ◽  
C Protein ◽  
Tissue Specific ◽  
Specific Outcome ◽  
C Proteins ◽  
Broad Complex

The steroid hormone ecdysone initiates metamorphosis in Drosophila melanogaster by activating a cascade of gene activity that includes primary response transcriptional regulators and secondary response structural genes. The Broad-Complex (BR-C) primary response gene is composed of several distinct genetic functions and encodes a family of related transcription factor isoforms. Our objective was to determine whether BR-C isoforms were components of the primary ecdysone response in all tissues and whether tissue-specific isoform expression is associated with tissue-specific metamorphic outcomes. We used specific antibody reagents that recognize and distinguish among the Z1, Z2 and Z3 BR-C protein isoforms to study protein expression patterns during the initial stages of metamorphosis. Western blot analyses demonstrated that BR-C isoforms are induced at the onset of metamorphosis, each with unique kinetics of induction and repression. Whole-mount immunostaining showed that the BR-C proteins accumulate in the nuclei of all larval and imaginal tissues indicating that the BR-C is induced as a primary response in many tissues. Several tissues express different levels and combinations of the BR-C isoforms suggesting that the BR-C is important in determining the tissue-specific outcome of many parallel ecdysone response cascades. For example, prepupal salivary glands (destined for histolysis during metamorphosis) express Z1 isoforms while imaginal discs (destined for cell differentiation and morphogenesis) shift from the synthesis of Z2 isoforms to the synthesis of Z1 isoforms. The prepupal central nervous system (destined for tissue remodeling) expresses all isoforms, with Z3 predominating. Salivary gland chromosome immunostaining indicated that BR-C proteins interact directly with numerous loci in the polytene genome. Finally, western blot analyses showed that distinct BR-C genetic functions can be correlated with single and specific BR-C protein isoforms.

scholarly journals Modified LDL Particles Activate Inflammatory Pathways in Monocyte-derived Macrophages: Transcriptome Analysis

2018 ◽  
Vol 24 (26) ◽  
pp. 3143-3151 ◽  
Author(s):  
Alexander N. Orekhov ◽  
Yumiko Oishi ◽  
Nikita G. Nikiforov ◽  
Andrey V. Zhelankin ◽  
Larisa Dubrovsky ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Atherosclerotic Lesion ◽  
Density Lipoprotein ◽  
Primary Response ◽  
Secondary Response ◽  
Modified Ldl ◽  
Ldl Particles ◽  
Regulator Genes ◽  
Lipid Metabolism Genes

Background: A hallmark of atherosclerosis is its complex pathogenesis, which is dependent on altered cholesterol metabolism and inflammation. Both arms of pathogenesis involve myeloid cells. Monocytes migrating into the arterial walls interact with modified low-density lipoprotein (LDL) particles, accumulate cholesterol and convert into foam cells, which promote plaque formation and also contribute to inflammation by producing proinflammatory cytokines. A number of studies characterized transcriptomics of macrophages following interaction with modified LDL, and revealed alteration of the expression of genes responsible for inflammatory response and cholesterol metabolism. However, it is still unclear how these two processes are related to each other to contribute to atherosclerotic lesion formation. Methods: We attempted to identify the main mater regulator genes in macrophages treated with atherogenic modified LDL using a bioinformatics approach. Results: We found that most of the identified genes were involved in inflammation, and none of them was implicated in cholesterol metabolism. Among the key identified genes were interleukin (IL)-7, IL-7 receptor, IL- 15 and CXCL8. Conclusion: Our results indicate that activation of the inflammatory pathway is the primary response of the immune cells to modified LDL, while the lipid metabolism genes may be a secondary response triggered by inflammatory signalling.

scholarly journals Hepatic Hilar Lymph Node Reactivity at Kasai Portoenterostomy for Biliary Atresia: Correlations With Age, Outcome, and Histology of Proximal Biliary Remnant

2017 ◽  
Vol 21 (1) ◽  
pp. 29-40 ◽  
Author(s):  
KE Bove ◽  
R Sheridan ◽  
L Fei ◽  
R Anders ◽  
CT Chung ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Biliary Atresia ◽  
Cystic Duct ◽  
Secondary Infection ◽  
Age At Onset ◽  
Primary Response ◽  
Antigenic Stimulation ◽  
Hilar Lymph Node ◽  
Proximate Cause ◽  
Congenital Biliary Atresia

We hypothesized that if infection is the proximate cause of congenital biliary atresia, an appropriate response to antigen would occur in lymph nodes contiguous with the biliary remnant. We compared the number of follicular germinal centers (GC) in 79 surgically excised hilar lymph nodes (LN) and 27 incidentally discovered cystic duct LNs in 84 subjects at the time of hepatic portoenterostomy (HPE) for biliary atresia (BA) to autopsy controls from the pancreaticobiliary region of non-septic infants >3 months old at death. All 27 control LN lacked GC, a sign in infants of a primary response to antigenic stimulation. GC were found in 53% of 106 LN in 56 of 84 subjects. Visible surgically excised LN contiguous with the most proximal biliary remnants had 1 or more well-formed reactive GC in only 26/51 subjects. Presence of GC and number of GC/LN was unrelated to age at onset of jaundice or to active fibroplasia in the biliary remnant but was related to older age at HPE. Absent GC in visible and incidentally removed cystic duct LNs predicted survival with the native liver at 2 and 3 years after HPE, P = .03, but significance was lost at longer intervals. The uncommon inflammatory lesions occasionally found in remnants could be secondary either to bile-induced injury or secondary infection established as obstruction evolves. The absence of consistent evidence of antigenic stimulation in LN contiguous with the biliary remnant supports existence of at least 1 major alternative to infection in the etiology of biliary atresia.

scholarly journals Personalised Profiling of Innate Immune Memory Induced by Nano-Imaging Particles in Human Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Giacomo Della Camera ◽  
Mariusz Madej ◽  
Anna Maria Ferretti ◽  
Rita La Spina ◽  
Yang Li ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Primary Response ◽  
Innate Immune ◽  
Engineered Nanoparticles ◽  
Secondary Response ◽  
Immune Memory ◽  
Immune Reactivity ◽  
Iron Oxide Particles ◽  
Lps Challenge

Engineered nanoparticles used for medical purposes must meet stringent safety criteria, which include immunosafety, i.e., the inability to activate possibly detrimental immune/inflammatory effects. Even medical nanomaterials devoid of direct immunotoxic or inflammatory effects may have an impact on human health if able to modify innate memory, which is the ability to “prime” future immune responses towards a different, possibly more detrimental reactivity. Although innate memory is usually protective, anomalous innate memory responses may be at the basis of immune pathologies. In this study, we have examined the ability of two nanomaterials commonly used for diagnostic imaging purposes, gold and iron oxide nanoparticles, to induce or modulate innate memory, using an in vitro model based on human primary monocytes. Monocytes were exposed in culture to nanoparticles alone or together with the bacterial agent LPS (priming phase/primary response), then rested for six days (extinction phase), and eventually challenged with LPS (memory/secondary response). The memory response to the LPS challenge was measured as changes in the production of inflammatory (TNFα, IL-6) and anti-inflammatory cytokines (IL-10, IL-1Ra), as compared to unprimed monocytes. The results show that both types of nanoparticles can have an effect in the induction of memory, with changes observed in the cytokine production. By comparing nanomaterials of different shapes (spherical vs. rod-shaped gold particles) and different size (17 vs. 22 nm diameter spherical iron oxide particles), it was evident that innate memory could be differentially induced and modulated depending on size, shape and chemical composition. However, the main finding was that the innate memory effect of the particles was strongly donor-dependent, with monocytes from each donor showing a distinct memory profile upon priming with the same particles, thereby making impossible to draw general conclusions on the particle effects. Thus, in order to predict the effect of imaging nanoparticles on the innate memory of patients, a personalised profiling would be required, able to take in consideration the peculiarities of the individual innate immune reactivity.

scholarly journals Idiotypic repertoire of anti-hen eggwhite lysozyme antibodies probed with hybridomas. Selection after immunization of an IdX marker common to antibodies of distinct epitope specificity.

1981 ◽  
Vol 154 (3) ◽  
pp. 701-712 ◽  
Author(s):  
D W Metzger ◽  
A Furman ◽  
A Miller ◽  
E E Sercarz
Keyword(s):  
Primary Response ◽  
Lymphoid Cells ◽  
Secondary Response ◽  
Epitope Specificity

A panel of hybridoma antibodies obtained from lymphoid cells that were fused during a primary response ("early") or a secondary response ("late") gave results concordant with analysis of conventional, in vivo-produced anti-lysozyme idiotypes: early antibodies did not display the predominant anti-hen eggwhite lysozyme idiotype (IdX-HEL), whereas late antibodies all displayed IdX-HEL. Furthermore, individual late hybridomas could each remove the entire anti-IdX-HEL activity by absorption, whereas early hybridomas could not. The epitope specificities of the hybridomas in both the early and late populations were heterogenous. We conclude that epitypic specificity in the response to HEL is determined independently from idiotypic specificity and that the predominant idiotype is selected for during the maturation of the anti-lysozyme response.

Cytodynamics and ontogeny of the immune reponse of Xenopus laevis against sheep erythrocytes

Development ◽  
1973 ◽  
Vol 29 (1) ◽  
pp. 73-85
Author(s):  
Gerald M. Kidder ◽  
Laurens N. Ruben ◽  
Jean M. Stevens
Keyword(s):  
Xenopus Laevis ◽  
Cell Response ◽  
Single Injection ◽  
Quantitative Measure ◽  
Peak Level ◽  
Primary Response ◽  
Secondary Response ◽  
Red Cell ◽  
Sheep Erythrocytes ◽  
Morphological Criteria

The heterologous red cell response of Xenopus laevis larvae and post-metamorphic toadlets was investigated by means of the immuno-cytoadherence (ICA) technique. Sheep erythrocytes (SRBC) were employed as immunogen. Toadlets responded to a single injection of immunogen within 4 days, and exhibited a peak level of rosette-forming cells (RFC) in their spleens at 8 days post-injection. Toadlets immunized against sheep erythrocytes gave only a very slight response when tested against rat erythrocytes. A secondary response, much greater in magnitude than the primary response, was evident within 2days when previously immunized toadlets were reinjected with the same immunogen. It was concluded that the ICA technique provides a quantitative measure of an acute immune response in these animals. Larvae which had passed through stage 50 of Nieuwkoop & Faber exhibited substantial increases in RFC in the spleens when tested 6–10 days after injection with sheep erythrocytes. Significantly increased frequencies of RFC in thymi were also noted in these larvae, but the numbers involved were very low and varied considerably. Histological observations of these larvae revealed lymphoid maturation of the spleens and thymi to be essentially complete. Larvae which had not reached stage 50 according to external morphological criteria, but whose lymphoid organs had matured to a degree equivalent to stage 50, also exhibited strong anti-SRBC response in the spleens. Response in the thymi was low and not statistically significant. Larvae injected at a stage when lymphocytic differentiation was complete in the thymi but had not begun in the spleens did not exhibit an elevated splenic RFC frequency when tested after the spleens had matured. These data suggest that the heterologous red cell response in the larval spleen is dependent upon antigenic challenge to spleens which have reached the stage 50 equivalent in their histogenesis.

scholarly journals Insights into the Metabolism of Elemental Sulfur by the Hyperthermophilic Archaeon Pyrococcus furiosus: Characterization of a Coenzyme A- Dependent NAD(P)H Sulfur Oxidoreductase

2007 ◽  
Vol 189 (12) ◽  
pp. 4431-4441 ◽  
Author(s):  
Gerrit J. Schut ◽  
Stephanie L. Bridger ◽  
Michael W. W. Adams
Keyword(s):  
Gene Cluster ◽  
Elemental Sulfur ◽  
Coenzyme A ◽  
Specific Activity ◽  
Pyrococcus Furiosus ◽  
Side Reaction ◽  
Primary Response ◽  
Secondary Response ◽  
Hyperthermophilic Archaeon ◽  
Membrane Bound

ABSTRACT The hyperthermophilic archaeon Pyrococcus furiosus uses carbohydrates as a carbon source and produces acetate, CO2, and H2 as end products. When S0 is added to a growing culture, within 10 min the rate of H2 production rapidly decreases and H2S is detected. After 1 hour cells contain high NADPH- and coenzyme A-dependent S0 reduction activity (0.7 units/mg, 85°C) located in the cytoplasm. The enzyme responsible for this activity was purified to electrophoretic homogeneity (specific activity, 100 units/mg) and is termed NAD(P)H elemental sulfur oxidoreductase (NSR). NSR is a homodimeric flavoprotein (M r, 100,000) and is encoded by PF1186. This designation was previously assigned to the gene encoding an enzyme that reduces coenzyme A disulfide, which is a side reaction of NSR. Whole-genome DNA microarray and quantitative PCR analyses showed that the expression of NSR is up-regulated up to sevenfold within 10 min of S0 addition. This primary response to S0 also involves the up-regulation (>16-fold) of a 13-gene cluster encoding a membrane-bound oxidoreductase (MBX). The cluster encoding MBX is proposed to replace the homologous 14-gene cluster that encodes the ferredoxin-oxidizing, H2-evolving membrane-bound hydrogenase (MBH), which is down-regulated >12-fold within 10 min of S0 addition. Although an activity for MBX could not be demonstrated, it is proposed to conserve energy by oxidizing ferredoxin and reducing NADP, which is used by NSR to reduce S0. A secondary response to S0 is observed 30 min after S0 addition and includes the up-regulation of genes encoding proteins involved in amino acid biosynthesis and iron metabolism, as well as two so-called sulfur-induced proteins termed SipA and SipB. This novel S0-reducing system involving NSR and MBX has been found so far only in the heterotrophic Thermococcales and is in contrast to the cytochrome- and quinone-based S0-reducing system in autotrophic archaea and bacteria.

scholarly journals Murine syngeneic mixed lymphocyte response. I. Target antigens are self Ia molecules

1981 ◽  
Vol 154 (5) ◽  
pp. 1652-1670 ◽  
Author(s):  
LH Glimcher ◽  
DL Longo ◽  
I Green ◽  
RH Schwartz
Keyword(s):  
T Cells ◽  
Culture Conditions ◽  
Primary Response ◽  
Secondary Response ◽  
Mouse Serum ◽  
Lymphocyte Response ◽  
Radiation Induced ◽  
Antigen Presenting

A system has been described that produces a murine syngeneic mixed lymphocyte response (MLR) comparable in magnitude to an allogeneic MLR. The responder cells in these cultures exhibit the classic immunologic characteristics of both memory and specificity. Studies using radiation-induced bone marrow chimeras of F(1) {arrow} parent type indicated that, similar to many other T cell-mediated immune responses, the response of the T lymphocytes in the syngeneic MLR was major histocompatibility complex-restricted and was determined by the environment in which the T cells matured. Using responder T cells from F(1) {arrow} parent chimeras and stimulator cells from H-2 recombinant strains, it was possible to map the genes involved in the stimulation to the K and/or I regions. In addition, blocking studies with monoclonal anti-Ia antibodies suggested that in the B10.A strain the critical molecules were products of both the I-A(k) and I-E(k) subregions. The issue of whether the syngeneic MLR is directed solely at self I-region antigens or whether the response represents proliferation to an unknown antigen in association with self I-region determinants was also addressed. Secondary syngeneic MLR were successfully performed in normal mouse serum and with stimulator cells prepared in the absence of bovine serum albumin to rule out the possibility that xenogeneic serum antigens were involved in the stimulation. The possibility that the syngeneic MLR might represent a secondary response to environmental antigens was eliminated by using germ- free mice as a source of stimulator cells and by demonstrating that spleen cells from unimmunized, fully allogeneic chimeras (B10.A {arrow} B10) could generate a normal syngeneic MLR even though such chimeras could not be primed to respond to any foreign antigens unless supplemented in vivo with a source of antigen-presenting cells syngeneic to the B10 host. The possibility that the syngeneic MLR was a primary response to a foreign antigen was considered unlikely because by using our culture conditions we could not obtain a primary antigen response or a secondary antigen response after in vitro priming to a variety of potent foreign antigens. Finally, the possibility that the syngeneic MLR represents a response to a variety of minor histocompatibility self antigens in association with self Ia molecules was eliminated by showing that the secondary responses to H-2 compatible, non-H-2 different strain (A/J vs. B10.A and C3H, or BALB/c vs. B10.D2 and DBA/2) were comparable to the secondary responses to syngeneic stimulators. Thus, we conclude that the target antigens in the syngeneic MLR are solely determinants on self Ia molecules, although the functionally equivalent possibility of a single, nonpolymorphic, minor self antigen seen in association with self Ia molecules cannot be excluded.

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