CD20 was the first B cell differentiation antigen identified, and CD20-specific mAbs are commonly used for the treatment of B cell malignancies and autoantibody-mediated autoimmune diseases. Despite this the role of CD20 in human B cell physiology has remained elusive. We describe here a juvenile patient with CD20 deficiency due to a homozygous mutation in a splice junction of the CD20 gene (also known as MS4A1) that results in "cryptic" splicing and nonfunctional mRNA species. Analysis of this patient has led us to conclude that CD20 has a central role in the generation of T cell-independent (TI) antibody responses. Key evidence to support this conclusion was provided by the observation that although antigen-independent B cells developed normally in the absence of CD20 expression, antibody formation, particularly after vaccination with TI antigens, was strongly impaired in the patient. Consistent with this, TI antipolysaccharide B cell responses were severely impeded in CD20-deficient mice. Our study therefore identifies what we believe to be a novel type of humoral immunodeficiency caused by CD20 deficiency and characterized by normal development of antigenindependent B cells, along with a reduced capacity to mount proper antibody responses.
Immune-checkpoint inhibitors (ICIs) activate the immune system to assault cancer cells in a manner that is not antigen specific. We hypothesized that tolerance may also be broken to autoantigens, resulting in autoantibody formation, which could be associated with immune-related adverse events (irAEs) and antitumor efficacy. Twenty-three common clinical autoantibodies in pre-and posttreatment sera from 133 ipilimumab-treated melanoma patients were determined, and their development linked to the occurrence of irAEs, best overall response, and survival. Autoantibodies developed in 19.2% (19/99) of patients who were autoantibody-negative pretreatment. A nonsignificant association was observed between development of any autoantibodies and any irAEs [OR, 2.92; 95% confidence interval (CI) 0.85-10.01]. Patients with antithyroid antibodies after ipilimumab had significantly more thyroid dysfunction under subsequent anti-PD-1 therapy: 7/11 (54.6%) patients with antithyroid antibodies after ipilimumab developed thyroid dysfunction under anti-PD1 versus 7/49 (14.3%) patients without antibodies (OR, 9.96; 95% CI, 1.94-51.1). Patients who developed autoantibodies showed a trend for better survival (HR for all-cause death: 0.66; 95% CI, 0.34-1.26) and therapy response (OR, 2.64; 95% CI, 0.85-8.16). We conclude that autoantibodies develop under ipilimumab treatment and could be a potential marker of ICI toxicity and efficacy.
In patients with B-cell chronic lymphocytic leukemia (B-CLL), the absolute number of T cells is increased. Although it has been suggested that these T cells might be tumor specific, concrete evidence for this hypothesis is lacking. We performed a detailed immunophenotypic analysis of the T-cell compartment in the peripheral blood of 28 patients with B-CLL (Rai 0, n ؍ 12; Rai I-II, n ؍ 10; Rai III-IV, n ؍ 6) and 12 healthy age-matched controls and measured the ability of these patients to mount specific immune responses. In all Rai stages a significant increase in the absolute numbers of CD3 ؉ cells was observed. Whereas the number of CD4 ؉ cells was not different from controls, patients with B-CLL showed significantly increased relative and absolute numbers of CD8 ؉ cells, which exhibited a CD45RA ؉ CD27 ؊ cytotoxic phenotype. Analysis of specific immune responses with tetrameric cytomegalovirus (CMV)-peptide complexes showed that patients with B-CLL had significantly increased numbers of tetramerbinding CMV-specific CD8 ؉ T cells. The rise in the total number of CD8 ؉ cytotoxic T cells was evident only in CMV-seropositive B-CLL patients. Thus, our data suggest that in patients with B-CLL the composition of T cells is shifted toward a CD8 ؉ cytotoxic cell type in an effort to control infections with persistent viruses such as CMV. Moreover, they offer an explanation for the high incidence of CMV reactivation in CLL patients treated with T cell-depleting agents, such as the monoclonal antibody (mAb) alemtuzumab (Campath; ␣-CD52 mAb). Furthermore, because in CMV-seronegative patients no increase in cytotoxic CD8 ؉ T cells is found, our studies do not support the hypothesis that tumor-specific T cells account for T-cell expansion in B-CLL.
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