Co-Inhibitory Molecules – Their Role in Health and Autoimmunity; Highlighted by Immune Related Adverse Events

Abstract

Immune checkpoint receptors are key players in regulating the immune response. They are responsible for both generating an immune response sufficient to kill invading pathogens, balancing the same response, and protecting against tissue destruction or the development of autoimmune events. The central role of the co-inhibitory receptors also referred to as inhibitory immune checkpoints, including PD-1 and CTLA-4 has become especially evident with the cancer treatments targeting these receptors. Blocking these pathways enhances the immune activity, resulting in both an increased chance of cancer clearance, at the same time induction of immune-related adverse events (irAE). Some of these irAE progress into actual autoimmune diseases with autoantibodies and symptoms, undistinguished from the naturally occurring diseases. This review will take advantage of the lessons learned from immune checkpoint blockade and relate this knowledge to our understanding of the same pathways in naturally occurring autoimmune diseases, mainly focusing on rheumatic diseases.

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…The formation of autoreactive B cells in the periphery is caused by a deficiency in the central tolerance mechanism of B cells. The increased number of autoaggressive B cells is also caused by mutations in PTPN22, BTK, and ADA, as well as impaired rearrangements of the BCR light chain and defects in TLRs [ 4 , 136 ]. Inhibition of PTPN22 influences T and B cell antigen-specific responses, dectin-1 activation in DCs, the formation and function of Tregs, macrophage responses controlled by NOD2, TLRs, and NLRP3, and neutrophil adherence and mast cell stimulation in an IgE-dependent way [ 137 ]; these functions make it a target for antitumor therapies.…”

Germline variants of the immune checkpoint proteins PD‐1, PD‐l1 and CTLA‐4 and immune tolerance induction outcome in patients with inherited haemophilia A

“…4 Beyond cancer immunotherapy, the establishment of peripheral self-tolerance are mainly orchestrated by these molecules, with surveillancet's disruption by altered expression or germline polymorphisms linked to cancer susceptibility 5 and autoimmune-related disorders. 6 Based on the proposed mechanism of PD-1/PD-L1 interaction to achieve FVIII tolerance 3 and the role of genetic variants in disease susceptibility/outcome, 5,6 we investigated the diversity of germline genetic alterations of immune checkpoint genes PDCD1 (PD-1), CD274…”

Encouraging probiotics for the prevention and treatment of immune-related adverse events in novel immunotherapies against malignant glioma

“…Those harmfulness might be frequently related to inflammatory effects and/or off-target immune effects. Some of the IRAEs could progress into actual autoimmune diseases with autoantibodies and/or symptoms fairly undistinguished from the naturally occurring autoimmune diseases [ 23 ], in which inflammatory mitochondrial dysfunction may be regarded as the core of their pathological processes [ 24 ]. It has been implicated that accelerating cancer progression may also remain a cause of concern [ 25 ].…”