Early B cell changes predict autoimmunity following combination immune checkpoint blockade

Das, Rituparna; Bar, Noffar; Ferreira, Michelle; Newman, Aaron M.; Zhang, Lin; Bailur, Jithendra Kini; Bacchiocchi, Antonella; Kluger, Harriet M.; Wei, Wei; Halaban, Ruth; Sznol, Mario; Dhodapkar, Madhav V.; Dhodapkar, Kavita M.

doi:10.1172/jci96798

Cited by 304 publications

(268 citation statements)

References 18 publications

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“…The pathogenesis and molecular mechanisms of irAEs are not well understood, although they could relate to preexisting autoimmunity or environmental factors . Notably, it is unclear why our patient experienced both epididymo‐orchitis and encephalitis.…”

Section: Discussionmentioning

confidence: 94%

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

et al. 2019

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Background Immune checkpoint inhibitors such as pembrolizumab and nivolumab have emerged as active treatment options for patients with many cancers, including metastatic melanoma, but can also cause symptomatic or life‐threatening immune‐related adverse events, including encephalitis. Epididymitis and orchitis are rare complications of these therapies. Case Presentation We describe herein a patient with metastatic melanoma who developed epididymo‐orchitis followed by encephalitis while receiving pembrolizumab. The patient developed testicular pain and fever after his third dose of pembrolizumab; ultrasound evaluation demonstrated bilateral epididymo‐orchitis. He then developed headaches, fever, and altered mental status over the next week and was admitted to the hospital. Lumbar puncture revealed inflammatory changes consistent with meningoencephalitis; he did not improve with broad‐spectrum antibiotics, and an extensive workup for infectious etiologies, including cerebrospinal fluid testing using a clinical metagenomic next‐generation sequencing assay, was negative. He received high‐dose steroids for suspected autoimmune encephalitis, and both his orchitis and meningoencephalitis improved rapidly after one dose. He fully recovered after a 5‐week taper of oral steroids. Discussion Here, we report a case of epididymo‐orchitis complicating immune checkpoint inhibitor therapy. This patient subsequently developed severe encephalitis but rapidly improved with steroids. Clinicians should be aware of rare complications of these agents. Key Points Epididymo‐orchitis is a rare and potentially life‐threatening complication of anti‐programmed death protein 1 (anti‐PD‐1) therapy. For patients on anti‐PD‐1 therapy who develop either epididymo‐orchitis or epididymitis without clear infectious cause, immune‐related adverse events should be considered in the differential diagnosis. If severe, epididymo‐orchitis related to anti‐PD‐1 therapy may be treated with high‐dose corticosteroids.

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Section: Discussionmentioning

confidence: 94%

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

et al. 2019

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“…Top right histograms: Comparative B-cell subset histogram profiles utilizing resting naive (rNAV) or DN2 B cells as references conclusively reveals that dominant T-bet expression resides in aNAV and DN2 B-cell fractions.SWM-(CD27 + IgD-CXCR5-CD11c+) and to a lesser extent SWM+ (CD27 + IgD-CXCR5 + CD11c-) have higher T-bet expression than rNAV but much less than aNAV and DN2 with checkpoint inhibitors in whom the expansion of these cells correlated with the risk of developing autoimmune complications 114. The combination of these markers, typically comprising IgD, IgM, CD27, CD38, and CD24, also allows discrimination of several CD27+ memory populations including: IgD+/IgM+ unswitched cells, IgMonly preswitch cells, class-switched cells predominantly comprised of IgG+ or IgA+ cells, and very small fractions of IgD-only and IgE+ cells.…”

mentioning

confidence: 99%

“…The combination of these markers, typically comprising IgD, IgM, CD27, CD38, and CD24, also allows discrimination of several CD27+ memory populations including: IgD+/IgM+ unswitched cells, IgMonly preswitch cells, class-switched cells predominantly comprised of IgG+ or IgA+ cells, and very small fractions of IgD-only and IgE+ cells. It is also important to note that in essentially all human studies,110,111,113,114 ABC-like cells were shown or postulated to represent CD27+-activated memory B cells. In contrast, in the context of persistent antigenic stimulation in either active SLE or chronic infections like HIV or malaria, the peripheral blood contains a substantially enlarged fraction of activated memory cells characterized by loss of CD21 and upregulation of CD80/CD86 and/or CD95.…”

mentioning

confidence: 99%

Extrafollicular responses in humans and SLE

Jenks

Cashman

Woodruff

et al. 2019

Immunological Reviews

195

197

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Summary Chronic autoimmune diseases, and in particular Systemic Lupus Erythematosus (SLE), are endowed with a long‐standing autoreactive B‐cell compartment that is presumed to reactivate periodically leading to the generation of new bursts of pathogenic antibody‐secreting cells (ASC). Moreover, pathogenic autoantibodies are typically characterized by a high load of somatic hypermutation and in some cases are highly stable even in the context of prolonged B‐cell depletion. Long‐lived, highly mutated antibodies are typically generated through T‐cell–dependent germinal center (GC) reactions. Accordingly, an important role for GC reactions in the generation of pathogenic autoreactivity has been postulated in SLE. Nevertheless, pathogenic autoantibodies and autoimmune disease can be generated through B‐cell extrafollicular (EF) reactions in multiple mouse models and human SLE flares are characterized by the expansion of naive‐derived activated effector B cells of extrafollicular phenotype. In this review, we will discuss the properties of the EF B‐cell pathway, its relationship to other effector B‐cell populations, its role in autoimmune diseases, and its contribution to human SLE. Furthermore, we discuss the relationship of EF B cells with Age‐Associated B cells (ABCs), a TLR‐7‐driven B‐cell population that mediates murine autoimmune and antiviral responses.

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“…Similar to RA, neutrophils are the predominant cell type seen in the synovial fluid of patients with ICI‐IA . Combination anti‐CTLA‐4 and anti‐PD1 therapy has also been shown to increase circulating plasmablast numbers and CXCL13 levels compared to either treatment alone, suggesting augmented germinal center activation . In addition, these patients had elevated levels of CD21‐low‐expressing B cells, which expressed higher levels of PD‐1 and were more clonal than CD21‐high B cells.…”

Section: Immune Dysregulationmentioning

confidence: 99%

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

Cappelli¹,

Thomas²,

Bingham³

et al. 2020

Immunological Reviews

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The development of inflammatory arthritis in patients receiving immune checkpoint inhibitor therapy is increasingly recognized due to the growing use of these drugs for the treatment of cancer. This represents an important opportunity not only to define the mechanisms responsible for the development of this immune‐related adverse event and to ultimately predict or prevent its development, but also to provide a unique window into early events in the development of inflammatory arthritis. Knowledge gained through the study of this patient population, for which the inciting event is known, could shed light into the pathogenesis of autoimmune arthritis. This review will highlight the clinical and immunologic features of these entities to define common elements for future study.

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Early B cell changes predict autoimmunity following combination immune checkpoint blockade

Cited by 304 publications

References 18 publications

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

Severe Epididymo-Orchitis and Encephalitis Complicating Anti-PD-1 Therapy

Extrafollicular responses in humans and SLE

Immune checkpoint inhibitor–induced inflammatory arthritis as a model of autoimmune arthritis

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