Abstract Human Fc receptor-like 6 (FCRL6) is discretely expressed by cytotoxic lymphocytes, has ITIM-based signaling potential, and interacts with MHC II. To investigate the biology of its counterpart in mice, a panel of FCRL6-specific monoclonal antibodies was generated. In contrast to its expression in humans, FCRL6 could not be detected on mouse NK or CD8+ T cells. Instead, the receptor marked a subpopulation of pro B cells in adult bone marrow. FCRL6+ cells were absent in Hardy Fr. A, but became evident in Fr. B, peaked in Fr. C, and diminished in Fr. C’. The developmentally regulated expression of FCRL6 was also indicated by the increased frequency of these pro B cells in RAG2-/- and λ5-/- mice. FCRL6+ pro B cells were slightly smaller by light scatter and expressed relatively lower levels of IL-7Rα compared to FCRL6- cells. In keeping with this phenotypic difference, FCRL6+ pro B cells responded less favorably to IL-7 stimulation. They also had relatively lower proliferative and cycling capacity. Exposure of purified FCRL6- pro B cells to cytokines important for early B lineage differentiation revealed that FCRL6 surface expression could be induced by IL-7 alone, but was augmented by the addition of SCF. Collectively, these results demonstrate that FCRL6 defines a unique subset of mouse pro B cells that competes poorly relative to cells lacking its expression and suggest that FCRL6 may distinguish a subset of biologically impaired pro B cells.
Chronic lymphocytic leukemia (CLL) patients have lower seroconversion rates and antibody titers following SARS-CoV-2 vaccination, but the reasons for this diminished response are poorly understood. Here, we studied humoral and cellular responses in 95 CLL patients and 30 healthy controls after two BNT162b2 or mRNA-2173 mRNA immunizations. We found that 42% of CLL vaccinees developed SARS-CoV-2-specific binding and neutralizing antibodies (NAbs), while 32% had no response. Interestingly, 26% were seropositive, but had no detectable NAbs, suggesting the maintenance of pre-existing endemic human coronavirus-specific antibodies that cross-react with the S2 domain of the SARS-CoV-2 spike. These individuals had more advanced disease. In treatment-naïve CLL patients, mRNA-2173 induced 12-fold higher NAb titers and 1.7-fold higher response rates than BNT162b2. These data reveal a graded loss of immune function, with pre-existing memory being preserved longer than the capacity to respond to new antigens, and identify mRNA-2173 as a superior vaccine for CLL patients.
Innate-like splenic marginal zone (MZ) and peritoneal cavity B1 B lymphocytes share critical responsibilities in humoral responses but have divergent B-cell receptor (BCR) signaling features. A discrete marker of these subsets with tyrosine-based dual regulatory potential termed “Fc receptor-like 5” (FCRL5) was investigated to explore this discrepancy. Although FCRL5 repressed the robust BCR activity that is characteristic of MZ B cells, it had no influence on antigen receptor stimulation that is blunted in peritoneal cavity-derived B1 B cells. The molecular basis for the receptor’s inhibitory function derived from recruitment of the Src homology-2 domain-containing tyrosine phosphatase 1 (SHP-1) to a cytoplasmic immunoreceptor tyrosine-based inhibitory motif. Surprisingly, mutagenesis of this docking site unearthed coactivation properties for FCRL5 that were orchestrated by independent association of the Lyn Src-family kinase with an intracellular immunoreceptor tyrosine-based activation motif-like sequence. FCRL5’s unique binary regulation directly correlated with SHP-1 and Lyn activity, which, like BCR function, differed between MZ and B1 B cells. These findings collectively imply a specialized counterregulatory role for FCRL molecules at the intersection of innate and adaptive immunity.
The recent identification of five human Fc receptor (FcR) homologs, hFcRH1–5, has extended the known FcR family and identified an unanticipated richness of the chromosome 1q region in genes encoding potential Ig‐binding proteins. In a database search for additional relatives of this family we identified expressed sequence tag representatives of a new FcR‐related molecule (hFcRX) and its mouse ortholog (mFcRX). The FcRX cDNAs were cloned from human lymph node and mouse spleen cDNA libraries. hFcRX is located centromeric of FcγRII and FcγRIII at 1q23, and its mouse ortholog resides in a syntenic region of chromosome 1. The genes encode proteins with 67% interspecies identity that lack both N‐linked glycosylation sites and transmembrane regions. Two of the four FcRX domains are Ig‐like, and share characteristics similar to FcγRI domains 2 and 3, having 28% overall extracellular identity with hFcγRI and 27% identity with mFcγRI respectively. FcRX transcripts are found primarily in secondary lymphoid tissues, where they are expressed by B lineage cells. FcRX thus may function as a secreted or intracellular protein in normal and neoplastic B cells.
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.
Fc receptor homolog 4 (FcRH4) is a B cell-specific member of the recently identified family of FcRHs whose intracellular domain contains three potential immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The signaling potential of this receptor, shown here to be preferentially expressed by memory B cells, was compared with the inhibitory receptor FcγRIIb in B cells expressing either WT FcγRIIb or chimeric proteins in which the intracellular domain of FcRH4 was fused to the transmembrane and extracellular domains of FcγRIIb. Coligation of the FcγRIIb/FcRH4 chimeric protein with the B cell receptor (BCR) led to tyrosine phosphorylation of the two membrane-distal tyrosines and profound inhibition of BCR-mediated calcium mobilization, whole cell tyrosine phosphorylation, and mitogen-activated protein (MAP)-kinase activation. Mutational analysis of the FcRH4 cytoplasmic region indicated that the two membrane-distal ITIMs are essential for this inhibitory potential. Phosphopeptides corresponding to these ITIMs could bind the Src homology 2 (SH2) domain-containing tyrosine phosphatases SHP-1 and SHP-2, which associated with the WT FcRH4 and with mutants having inhibitory capability. These findings indicate the potential for FcRH4 to abort B cell receptor signaling by recruiting SHP-1 and SHP-2 to its two membrane distal ITIMs.
154 Background: New treatments for chronic lymphocytic leukemia (CLL) with excellent response rates and varying toxicity profiles have emerged in recent years, creating an opportunity for a patient’s personal preferences to contribute to treatment decisions. Methods: We conducted a prospective, quasi-experimental pre- and post-evaluation of a multi-level educational program and its impact on knowledge of CLL as well as on shared decision-making. We educated patients, patient navigators, and providers (nurses and physicians) using a combination of print, video, in-person lectures, and online case-based education tailored to each learner group. Patients were evaluated for change in patient activation, distress levels, desired role in decision-making, perception of decision-making, satisfaction with oncologist explanation of treatment choice, and knowledge of CLL. Patient navigators and providers were evaluated for change in CLL knowledge and perception of shared decision-making. Results: Forty-one patients and 87 providers participated in the educational program. We observed trends toward improved patient activation with 68% before education vs. 76% after education reporting a high (score of 3 or 4) Patient Activation Measure (PAM) . The percentage of patients desiring and perceiving shared decision-making trended upward from 47% to 67% and 35% to 49%, respectively. There was a trend toward an increase in the percentage of patients understanding that CLL is incurable (80% to 90%) and reporting awareness of signs of progression (64% to 76%). Patients satisfaction with their oncologist’s explanation of therapy increased significantly from 83% to 95% (p = 0.03). Conclusions: This modestly sized project demonstrated trends toward improvements in patient engagement, prognostic awareness, knowledge of signs of progression, and shared decision-making; these promising findings should be tested in larger samples. However, there remains an opportunity for further improvement in shared decision-making.
New treatments for chronic lymphocytic leukemia (CLL) with excellent response rates and varying toxicity profiles have emerged in recent years, creating an opportunity for a patient's personal preferences to contribute to treatment decisions. We conducted a prospective, quasi-experimental pre- and post-evaluation of a multilevel educational program and its impact on knowledge of CLL and shared decision-making (SDM). We educated patients, lay navigators, nurses/advanced practice providers (APPs), and physicians. Patients were evaluated for change in patient activation, distress, desired role in decision-making, perception of decision-making, satisfaction with oncologist explanation of treatment choice, and knowledge of CLL. Lay navigators, nurses/APPs, and physicians were evaluated for change in CLL knowledge and perception of decision-making. Forty-four patients, 33 lay navigators, 27 nurses/APPs, and 27 physicians participated in the educational program. We observed trends toward improved patient activation, with 68% before education versus 76% after education reporting a Patient Activation Measure (PAM) score of 3 or 4. The percentage of patients desiring and perceiving SDM trended upward from 47% to 67% and from 35% to 49%, respectively. The percentage of patients understanding that CLL is incurable increased from 80% to 90%, as did reporting awareness of signs of progression (64% to 76%). Patients' satisfaction with their oncologists' explanations of therapy increased significantly from 83% to 95% (p = .03). CLL knowledge increased after education for lay navigators (36% vs 63%) and nurses/APPs (35% vs 69%), and remained high for physicians (85% vs 87%). Nurses/APPs and physicians perceived at least some patient involvement in decision-making at baseline, whereas 12% of patients and 23% of lay navigators perceived that physicians made decisions independently. This project demonstrated trends toward improvements in patient engagement, prognostic awareness, knowledge of signs of progression, and SDM. These promising findings should be tested in larger samples. There remains an opportunity for further improvement in SDM.
