Impaired Antigen Presentation as Immune Escape Mechanism in Acute Myeloid Leukemia

Ossenkoppele, G.J. [Promotor]Loosdrecht, A.A. van de [Copromotor]Ham, S.M. van [Copromotor

B and T Cells Driving Multiple Sclerosis: Identity, Mechanisms and Potential Triggers

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS

Epstein-Barr virus and genetic risk variants as determinants of T-bet⁺ B cell-driven autoimmune diseases

B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such 'atypical' memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet+ B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein-Barr virus (EBV). The impact of EBV on T-bet+ B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet+ B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet+ B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet+ B-cell formation.</p

Tumor immune escape in acute myeloid leukemia: Class II-associated invariant chain peptide expression as result of deficient antigen presentation

In this overview, we discuss the role of class II-associated invariant chain peptide (CLIP) in acute myeloid leukemia (AML), one of the few tumors expressing HLA class II. The clinical impact, function and regulation of CLIP expression on leukemic cells is addressed, indicating its potential as immunotherapeutic target in AML

Ocrelizumab associates with reduced cerebrospinal fluid B and CD20^dim CD4⁺ T cells in primary progressive multiple sclerosis

The anti-CD20 monoclonal antibody ocrelizumab reduces disability progression in primary progressive multiple sclerosis. CD20 is a prototypical B-cell marker; however, subpopulations of CD4 + and CD8 + T cells in peripheral blood and cerebrospinal fluid also express low levels of CD20 (CD20 dim). Therefore, direct targeting and depletion of these CD20 dim T-cell subpopulations may contribute to the therapeutic effect of ocrelizumab. The aim of this observational cohort study was to compare CD20 + B-cell and CD20 dim T-cell distributions between peripheral blood and cerebrospinal fluid of ocrelizumab-treated or ocrelizumab-untreated people with primary progressive multiple sclerosis. Ocrelizumab treatment was associated with depletion of circulating B cells and CD20 dim CD4 + and CD20 dim CD8 + T cells (P &lt; 0.0001, P = 0.0016 and P = 0.0008, respectively) but, in cerebrospinal fluid, only with lower proportions of B cells and CD20 dim memory CD4 + T cells (P &lt; 0.0001 and P = 0.0043, respectively). The proportional prevalence of cerebrospinal fluid CD20 dim memory CD8 + T cells was not significantly reduced (P = 0.1333). Only in cerebrospinal fluid, the proportions of CD20 dim cells within CD4 + and not CD8 + T cells positive for CCR5, CCR6 and CXCR3 were reduced in ocrelizumab-treated participants. The proportion of CD20 dim CD4 + T cells and abundance of CD4 + relative to CD8 + T cells in cerebrospinal fluid correlated positively with age (R = 0.6799, P = 0.0150) and Age-Related Multiple Sclerosis Severity score (R = 0.8087, P = 0.0014), respectively. We conclude that, in contrast to cerebrospinal fluid CD20 dim CD8 + T cells, B cells and CD20 dim CD4 + T cells are reduced in cerebrospinal fluid of people with primary progressive multiple sclerosis with an ocrelizumab-associated depletion of circulating B cells and CD20 dim T cells. Therefore, these cells are likely to contribute to the therapeutic effects of ocrelizumab in people with primary progressive multiple sclerosis.</p