A congenic, non-obese diabetic (NOD) mouse strain that contains a segment of chromosome 3 from the diabetes-resistant mouse strain B6.PL-Thy-1a was less susceptible to diabetes than NOD mice. A fully penetrant immunological defect also mapped to this segment, which encodes the high-affinity Fc receptor for immunoglobulin G (IgG), Fc gamma RI. The NOD Fcgr1 allele, which results in a deletion of the cytoplasmic tail, caused a 73 percent reduction in the turnover of cell surface receptor-antibody complexes. The development of congenic strains and the characterization of Mendelian traits that are specific to the disease phenotype demonstrate the feasibility of dissecting the pathophysiology of complex, non-Mendelian diseases.

Summary Distinct differences in the capacity of monocyte FcyRII of different individuals to bind or not bind mouse IgGl defines a polymorphism ot FcyRIIa and has previously been defined as the high responder (HR) or low responder (LR) polymorphism of FcyRII. The precise definition of the molecular basis of the human HR/LR polymorphism of FcyRIIa from the peripheral blood mononuclear cells of normal individuals has been determined by anti-CD3 induction of T cell proliferation, the polymerase chain reaction {PCR), nucleotide sequencing, transfection and IgG binding. Amplification of first strand cDNA from mRNA isolated from mononuclear cells was performed by PCR using primers specific for the sequences encoding the leader and cytoplasmic sequences of FcyRUa, which is normally expressed in monocytes. Sequencing of the PCR products and transfection of these to FcyR cells indicated that in FcyRIIa of HR or LR individuals; (i) three nucieotide substitutions (CA to TG and G to A) resulted in the change of glutamine to tryptophan at position 27 {first extracellular domain) and arginine to histidine at position 131 (second extracellular domain); (ii) expression of cDNA encoding the various combinations of these indicated that arginine at position 131 was essential for IgGl binding whereas the amino acid changes at position 27 had no effect; and (iii) IgGl at high concentration bound to al! allomorphic forms of FcyRIIa. These results indicate that position 131 in the second extracellular domain of FcyRIIa is intimately involved in immunoglobulin binding. Furthermore, the apparent inability oi IgGl to bind to FcyRIIa of non-responder individuals is not absolute in that immune complexes sensitized with a high concentration of MlgGl will bind to non-responder-type FcyRIIa.

Background Sublingual immunotherapy (SLIT) for grass pollen allergy can modify the natural history of allergic rhinitis and is associated with increased allergen‐specific IgG4. IgG4 competitively inhibits functional IgE on the surface of effector cells, such as mast cells and basophils, from binding to allergens. To further understand the important role memory B‐cell (Bmem) responses play in mediating the beneficial effects of SLIT, we assessed changes in allergen‐specific Bmem subsets induced by SLIT for grass pollen allergy. Methods Blood samples were collected twice outside the pollen season from twenty‐seven patients with sensitization to ryegrass pollen (RGP; Lolium perenne) and seasonal rhinoconjunctivitis. Thirteen received 4‐month pre‐seasonal SLIT for grass pollen allergy, and 14 received standard pharmacotherapy only. Single‐cell RNA sequencing was performed on FACS‐purified Lol p 1‐specific Bmem before and after SLIT from four patients, and significant genes were validated by flow cytometry on the total cohort. Results Four months of SLIT increased RGP‐specific IgE and IgG4 in serum and induced two Lol p 1‐specific Bmem subsets with unique transcriptional profiles. Both subsets had upregulated expression of beta 1 integrin ITGB1 (CD29), whereas IGHE (IgE), IGHG4 (IgG4), FCER2 (CD23), and IL13RA1 were upregulated in one subset. There was an increase in the proportion of Lol p 1+ Bmem expressing surface IgG4, CD23, and CD29 after SLIT. Conclusions A clinically successful 4 months course of SLIT for grass pollen allergy induces two transcriptionally unique Bmem fates. Associated changes in surface‐expressed proteins on these Bmem subsets can be used as early biomarkers for treatment effects.