Andrew J. Gross

EBV and Systemic Lupus Erythematosus: A New Perspective

We have proposed that EBV uses mature B cell biology to access memory B cells as a site of persistent infection. A central feature of this model is that EBV adapts its gene expression profile to the state of the B cell it resides in and that the level of infection is stable over time. This led us to question whether changes in the behavior or regulation of mature B cells would alter the state of EBV persistence. To investigate this, we studied the impact of systemic lupus erythematosus (SLE), a disease characterized by immune dysfunction, on EBV infection. We show that patients with SLE have abnormally high frequencies of EBV-infected cells in their blood, and this is associated with the occurrence of SLE disease flares. Although patients with SLE have frequencies of infected cells comparable to those seen in immunosuppressed patients, in SLE the effect was independent of immunosuppressive therapy. Aberrant expression of viral lytic (BZLF1) and latency (latency membrane proteins 1 and 2a) genes was also detected in the blood of SLE patients. We conclude that the abnormal regulation of EBV infection in SLE patients reflects the sensitivity of the virus to perturbation of the immune system.

Developmental Acquisition of the Lyn-CD22-SHP-1 Inhibitory Pathway Promotes B Cell Tolerance

To better understand whether autoimmunity in Lyn-deficient mice arises from compromised central or peripheral B cell tolerance, we examined BCR signaling properties of wild-type and Lyn-deficient B cells at different stages of development. Wild-type mature follicular B cells were less sensitive to BCR stimulation than were immature transitional stage 1 B cells with regard to BCR-induced calcium elevation and ERK MAPK activation. In the absence of Lyn, mature B cell signaling was greatly enhanced, whereas immature B cell signaling was minimally affected. Correspondingly, Lyn deficiency substantially enhanced the sensitivity of mature B cells to activation via the BCR, but minimally affected events associated with tolerance induction at the immature stage. The effects of CD22 deficiency on BCR signaling were very similar in B cells at different stages of maturation. These results indicate that the Lyn-CD22-Src homology region 2 domain-containing phosphatase-1 inhibitory pathway largely becomes operational as B cell mature, and sets a threshold for activation that appears to be critical for the maintenance of tolerance in the B cell compartment.

Requirement for MyD88 Signaling in B Cells and Dendritic Cells for Germinal Center Anti-Nuclear Antibody Production in Lyn-Deficient Mice

The intracellular tyrosine kinase Lyn mediates inhibitory receptor function in B cells and myeloid cells, and Lyn−/− mice spontaneously develop an autoimmune and inflammatory disease that closely resembles human systemic lupus erythematosus. TLR-signaling pathways have been implicated in the production of anti-nuclear Abs in systemic lupus erythematosus and mouse models of it. We used a conditional allele of Myd88 to determine whether the autoimmunity of Lyn−/− mice is dependent on TLR/MyD88 signaling in B cells and/or in dendritic cells (DCs). The production of IgG anti-nuclear Abs, as well as the deposition of these Abs in the glomeruli of the kidneys, leading to glomerulonephritis in Lyn−/− mice, were completely abolished by selective deletion of Myd88 in B cells, and autoantibody production and glomerulonephritis were delayed or decreased by deletion of Myd88 in DCs. The reduced autoantibody production in mice lacking MyD88 in B cells or DCs was accompanied by a dramatic decrease in the spontaneous germinal center (GC) response, suggesting that autoantibodies in Lyn−/− mice may depend on GC responses. Consistent with this view, IgG anti-nuclear Abs were absent if T cells were deleted (TCRβ−/− TCRδ−/− mice) or if T cells were unable to contribute to GC responses as the result of mutation of the adaptor molecule SAP. Thus, the autoimmunity of Lyn−/− mice was dependent on T cells and on TLR/MyD88 signaling in B cells and in DCs, supporting a model in which DC hyperactivity combines with defects in tolerance in B cells to lead to a T cell–dependent systemic autoimmunity in Lyn−/− mice.

Elevated BCR signaling and decreased survival of Lyn-deficient transitional and follicular B cells

The Src‐family tyrosine kinase Lyn negatively regulates BCR signaling and also myeloid cell activity. Mice deficient in Lyn have substantially decreased numbers of peripheral B cells, despite spontaneously producing IgG anti‐DNA antibodies. Here, we examine the mechanism underlying the B‐cell depletion in these mice. Lyn‐deficient B cells were out‐competed by WT B cells in mixed BM chimeras at two steps, at the T1 to T2 transitional maturation stage in the spleen and again between the T2 or T3 stage and the mature follicular B‐cell population. Lyn‐deficient T2 and follicular B cells expressed elevated levels of the pro‐apoptotic factor Bim and deletion of Bim restored splenic B cells of Lyn‐deficient mice to close to WT numbers. Lyn‐deficient T2 and later stage B cells also had changes in cell surface phenotype consistent with increased in vivo BCR signaling. Similarly, an increased proportion of T2 and follicular B cells had elevated basal intracellular free calcium levels. Overall, these observations suggest that increased BCR signaling is responsible for increased death of weakly self‐reactive Lyn‐deficient B cells both at the T2 stage and additionally as these cells mature to follicular B cells.

Lyn deficiency affects B-cell maturation as well as survival.

Lyn, an Src‐family protein tyrosine kinase expressed in B lymphocytes, contributes to initiation of BCR signaling and is also responsible for feedback inhibition of BCR signaling. Lyn‐deficient mice have a decreased number of follicular B cells and also spontaneously develop a lupus‐like autoimmunity. We used flow cytometric analysis, BrdU labeling and our mathematical models of B‐cell population dynamics, to analyze how Lyn deficiency impacts B‐cell maturation and survival. We found that Lyn‐deficient transitional 1 (T1) cells develop normally, but T2 cells develop primarily from the T1 subset in the spleen and fail to also develop directly from BM immature B cells. Lyn‐deficient T2 cells either mature to the follicular B‐cell type at a close to normal rate, or die in this compartment rather than access the T3 anergic subset. The ∼40% of WT follicular cells that were short‐lived exited primarily by joining the T3 anergic subset, whereas the ∼15% Lyn−/− follicular cells that were not long lived had a high death rate and died in this compartment rather than entering the T3 subset. We hypothesize that exaggerated BCR signaling resulting from weak interactions with self‐antigens is largely responsible for these alterations in Lyn‐deficient B cells.

Oropharyngeal carcinoma arising after methotrexate and etanercept therapy for rheumatoid arthritis

Etanercept is an anti-tumor necrosis factor α receptor agent used to treat inflammatory conditions. Previous reports described rapid development of skin squamous cell carcinoma (SCC) after etanercept use. This report describes a novel case of oropharyngeal SCC associated with the use of etanercept. A 45-year-old man with rheumatoid arthritis developed oropharyngeal pain within 2 months after the start of etanercept therapy and was diagnosed with tonsillar carcinoma. This patient had other exposures that increase the risk of oropharyngeal cancer, such as tobacco and alcohol use. However, owing to the timing of onset of his initial symptoms, etanercept should be considered as a possible factor in the etiology or progression of his tumor, especially in the context of reported skin SCC after etanercept therapy in patients at risk for SCC. Clinicians should be alert to signs of malignancy in patients on etanercept, particularly those at high risk for skin or head and neck cancers.

Validity and Responsiveness of a 10-Item Patient-Reported Measure of Physical Function in a Rheumatoid Arthritis Clinic Population

We assessed implementation of the 10‐item Patient‐Reported Outcomes Measurement Information System (PROMIS) physical function form (PF‐10a) in routine practice in a racially and ethnically diverse population with rheumatoid arthritis (RA). Objectives were to determine feasibility of implementing PF‐10a in the electronic health record (EHR) and PF‐10a validity and longitudinal responsiveness.

Gingival pustules and sterile diffuse sclerosing osteomyelitis as a feature of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome represents the rare co-occurrence of sterile inflammatory osteoarticular disease in association with a variety of cutaneous manifestations. Oral involvement is uncommon. The etiology of SAPHO is complex and is likely the combined result of infectious, genetic, and immunologic factors. Due to diverse clinical presentations, SAPHO is difficult to diagnose. Here, we describe the case of a 74-year-old man, who had a history of SAPHO syndrome and presented with gingival pustules and sterile diffuse sclerosing osteomyelitis of the mandible. This is the first case report describing neutrophilic mucositis as a feature of SAPHO.

Endoscopy is of low yield in the identification of gastrointestinal neoplasia in patients with dermatomyositis: A cross-sectional study

AIM To determine the prevalence of gastrointestinal neoplasia among dermatomyositis patients who underwent an esophagogastroduodenoscopy and/or colonoscopy. METHODS A cross-sectional study examining the results of upper endoscopy and colonoscopy in adults with dermatomyositis at an urban, university hospital over a ten year period was performed. Chart review was performed to confirm the diagnosis of dermatomyositis. Findings on endoscopy were collected and statistical analyses stratified by age and presence of symptoms were performed. RESULTS Among 373 adult patients identified through a code based search strategy, only 163 patients had dermatomyositis confirmed by chart review. Of the 47 patients who underwent upper endoscopy, two cases of Barrett’s esophagus without dysplasia were identified and there were no cases of malignancy. Of the 67 patients who underwent colonoscopy, no cases of malignancy were identified and an adenoma was identified in 15% of cases. No significant differences were identified in the yield of endoscopy when stratified by age or presence of symptoms. CONCLUSION The yield of endoscopy is low in patients with dermatomyositis and is likely similar to the general population; we identified no cases of malignancy. A code based search strategy is inaccurate for the diagnosis of dermatomyositis, calling into question the results of prior population-based studies. Larger studies with rigorously validated search strategies are necessary to understand the risk of gastrointestinal malignancy in patients with dermatomyositis.

Omental infarction preceded by anatomically upturned omentum

We report the case of a 49-year-old man who presented with acute abdominal pain. Contrast-enhanced computed tomography of the abdomen revealed spontaneous omental torsion with no other noticeable findings. Notably, a computed tomography exam 6 months prior demonstrated the omentum located within the anterior hepatic space, suggesting that the patient had a hypermobile, upturned omentum. To our knowledge, this is the first case report illustrating an anatomically upturned omentum as precursor to omental infarction.