Faculty Bibliography

Programmed death-1 (PD-1) is a co-receptor that is expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. A major functional role of the PD-1 signaling pathway is the inhibition of self-reactive T cells, which serve to protect against autoimmune disease. Elimination of the PD-1 pathway can therefore result in the breakdown of immune tolerance that can ultimately lead to the development of pathogenic autoimmunity. Conversely, tumor cells can at times co-opt the PD-1 pathway to escape from immunosurveillance mechanisms. Therefore, blockade of the PD-1 pathway has become an attractive target in cancer therapy. Recent clinical trials have shown that anti-PD-1 agents have profound effects on solid tumor regression. Current approaches include six agents that are either PD-1 and PD-L1 targeted neutralizing antibodies or fusion proteins. More than forty clinical trials are underway to better define the role of PD-1 blockade in variety of tumor types. In this review we will highlight the basic biology of the PD-1 system and discuss its potential roles in both autoimmunity and cancer. We propose that future research on PD-1 may lead to the translation of fundamental regulatory pathways into the development of practical new approaches for the treatment of autoimmune diseases and cancer.

Noninvasive carotid measurements have proven value in the estimation of future cardiovascular (CV) outcomes in systemic lupus erythematosus (SLE). Natural IgM-antibodies to phosphorylcholine (PC) epitopes can enhance apoptotic-cell clearance and induce anti-inflammatory pathways. Herein, we show that subclinical CV disease, as detected by carotid ultrasound, in a cross-sectional SLE cohort was associated with lower levels of IgM anti-PC, as well as lower levels of the ratio of IgM anti-PC/total IgM, compared to patients without plaque (p=0.004 and p=0.02, respectively). The IgM anti-PC/total IgM association remained significant after adjusting for age, cholesterol and hypertension. Adiponectin and sE-selectin were significantly elevated in patients with plaque, and statistical models showed that combining adiponectin, sE-selectin and IgM anti-PC/total IgM was better for predicting plaque than either test alone. These results support the hypothesis that IgM-natural autoantibodies may inhibit atherogenesis, and confirm the utility of IgM anti-PC levels as a biomarker for subclinical CV disease.

Natural IgM are highly represented in the circulation at birth, and these often autoreactive antibodies have been postulated to have innate-like properties and play crucial roles in apoptotic cell clearance, tissue homeostasis, and immune modulation. This review summarizes the known properties of these IgM autoantibodies, and the evidence that these anti-apoptotic cell IgM natural antibodies can regulate inflammatory responses through ancient pathways of the innate immune system that first arose long before the initial emergence of the adaptive immune system. While the regulatory contributions of these natural IgM autoantibodies are certainly not an essential and fundamental component of host defenses, these provide an additional layer to further protect the host. More importantly, these IgM antibody responses are highly inducible and their up-regulation can be a powerful means for the host to survive in a setting of chronic inflammation. The observed beneficial clinical associations for cardiovascular disease and autoimmunity, as well as opportunities for potential therapeutic implications are discussed.

Autoreactive antibodies that recognize neo-determinants on apoptotic cells in mice have been proposed to have protective, homeostatic and immunoregulatory properties, although our knowledge about the equivalent antibodies in humans has been much more limited. In the current study, human monoclonal antibodies with binding specificity for apoptotic cells were isolated from the bone marrow of healthy adults using phage display technology. These antibodies were shown to recognize phosphorylcholine (PC)-associated neo-determinants. Interestingly, three of the four identified apoptotic cell-specific antibody clones were encoded by VH3 region rearrangements with germline or nearly germline configuration without evidence of somatic hypermutation. Importantly, the different identified antibody clones had diverse heavy chain CDR3 and deduced binding surfaces as suggested by structure modeling. This may suggest a potentially great heterogeneity in human antibodies recognizing PC-related epitopes on apoptotic cells. To re-construct the postulated structural format of the parental anti-PC antibody, the dominant clone was also expressed as a recombinant human polymeric IgM, which revealed a substantially increased binding reactivity, with dose-dependent and antigen-inhibitable binding of apoptotic cells. Our findings may have implication for improved prognostic testing and therapeutic interventions in human inflammatory disease.

Objectives To study infection rates in patients with low immunoglobulin (Ig) serum concentrations following administration of rituximab (RTX) in RA clinical trials. Methods Pooled analysis of RA clinical trial data from patients who developed low IgM or IgG (defined as below lower limit of normal [LLN] for >4 mths [or 2 consecutive study visits]) after >1 RTX course. Igs were generally measured every 8-16 wks. Patients with low Ig were permitted to receive RTX re-treatment courses. Infection rates were assessed before and during/after low IgM/IgG. Low IgG/IgM at baseline screening (IgG <5.65 and IgM <0.55 mg/mL) were exclusion criteria for entry into the trials. Results Of 3194 patients who had received up to 17 RTX courses over 9.5 yrs, 22.4% (n=717) developed low IgM and 3.5% (n=112) developed low IgG for >4 mths. All had measurable Ig levels. No increases in overall infection rates were observed in patients during/after low IgM/IgG vs before documentation of low Ig (Table). For IgG, serious infection (SIE) rates were similar before and during/after low IgG, but both were significantly higher than in patients who never developed low IgG. At baseline these patients were on average older, had longer disease duration, lower mean CD19+ count, lower mean IgG levels (8.4 vs 13.2 mg/mL) and had received more non-biologic DMARDs vs those who did not develop low IgG. Baseline oral steroid use was similar across sub-groups. For IgM, SIE rates were not significantly higher during/after low IgM vs before low IgM, and were similar to rates in patients who never developed low IgM. In patients with low IgG or IgM, the SIE profile was consistent with RTX clinical experience as most infections affected the lower respiratory tract. Analysis of SIE onset in relation to timing of low Ig was limited due to discrete protocol-defined time points for Ig assessments. Other limitations included low patient numbers in some subgroups and lack of placebo comparator. (Table Presented) Conclusions Following RTX treatment, !

The adaptive immune system augments host defenses against diverse infectious threats, yet also carries intertwined risks for the development of autoimmune disease. The immune system incorporates homeostatic pathways for essential housekeeping functions that involve recognition of oxidation-modified endogenous molecules. Now, the properties of a physiological class of natural autoantibodies, which seem to modulate the severity or even prevent the onset of autoimmune disease, are beginning to be defined. Whereas disease-associated IgG autoantibodies to nuclear antigens and citrulline-modified self-proteins have been shown to activate innate pattern recognition receptors leading to increased cell death and tissue injury, a class of IgM autoantibodies to oxidation-associated neo-antigens can oppose these pathogenic effects. These naturally arising regulatory IgM autoantibodies enhance the capacity for the phagocytic clearance of host cells affected by programmed death pathways. These antibodies can also suppress key signalling pathways in the innate immune system involved in the control and resolution of inflammatory responses to Toll-like receptor agonists and disease-associated IgG autoantibodies.