Seminars in Immunopathology最新文献

Somatic mutations in hematopoietic stem cells are common with aging and can result in expansion of clones harboring mutations, termed clonal hematopoiesis. This results in an increased risk of blood cancers but has also been linked with chronic inflammatory disease states. In recent years, clonal hematopoiesis has been established to have a causative role in atherogenesis and cardiovascular disease. Additionally, as the effector cells have been identified to be immune cells, there is ongoing interest in assessing whether dysregulated immune function plays a role in other chronic inflammatory conditions such as rheumatologic disease. Here, we summarize current understanding of clonal hematopoiesis with a focus on cardiovascular disease and inflammation while outlining the potential, yet unexplored, relationship between clonal hematopoiesis and autoimmune disease. Hematopoietic stem cells (HSCs) continually regenerate blood cells. Acquisition of a somatic mutation that provides a selective advantage, a driver mutation, can result in clonal expansion. Clonal hematopoiesis of indeterminate potential, where somatic mutations in certain cancer-associated genes result in clonal expansion in the absence of overt malignancy, can result in atherosclerotic cardiovascular disease in multiple vascular beds, inflammation, and may also contribute to the pathogenesis of autoimmune disease. Many questions remain unanswered regarding the relationship between clonal hematopoiesis and inflammatory disorders.

The discovery of anti-neutrophil cytoplasmic antibodies (ANCA) and their antigenic targets, myeloperoxidase (MPO) and proteinase 3 (PR3), has led to further understanding as to the pathophysiologic processes that underlie vascular and tissue damage in ANCA vasculitis. ANCA trigger neutrophil activation leading to vascular damage in ANCA vasculitis. However, decades of study have determined that neutrophil activation alone is not sufficient to cause disease. Inflammatory stimuli are drivers of ANCA autoantigen expression and ANCA production. Certain infections or bacterial peptides may be crucial players in the initial steps of ANCA immunopathogenesis. Genetic and epigenetic alterations of gene encoding for MPO and PR3 provide additional disturbances to the immune homeostasis which provide a substrate for pathogenic ANCA formation from an adaptive immune system predisposed to autoreactivity. Promoted by inflammatory cytokines, ANCA binding leads to neutrophil activation, a process characterized by conformational changes, production and release of cytotoxic substances, and alternative complement pathway activation, thus creating an intense inflammatory milieu. This cascade of events perpetuates a vicious cycle of further inflammatory cell recruitment and activation, culminating in tissue necrosis. Our understanding of the pathogenic process in ANCA vasculitis paves the way for the development of therapies targeting crucial steps in this process. The greater appreciation of the role for complement, monocytes, and the adaptive immune system has already led to novel complement blockers and is poised to lead to further innovations which will allow for tailored antigen- or cell-specific immunotherapy targeting the autoimmune process without exposure to undue risks or toxicities.

Two vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are recognized as autoimmune and autoinflammatory diseases that manifest exclusively within the aorta and its large branches. In both entities, the age of the affected host is a critical risk factor. TAK manifests during the 2nd-4th decade of life, occurring while the immune system is at its height of performance. GCA is a disease of older individuals, with infrequent cases during the 6th decade and peak incidence during the 8th decade of life. In both vasculitides, macrophages and T cells infiltrate into the adventitia and media of affected vessels, induce granulomatous inflammation, cause vessel wall destruction, and reprogram vascular cells to drive adventitial and neointimal expansion. In GCA, abnormal immunity originates in an aged immune system and evolves within the aged vascular microenvironment. One hallmark of the aging immune system is the preferential loss of CD8⁺ T cell function. Accordingly, in GCA but not in TAK, CD8⁺ effector T cells play a negligible role and anti-inflammatory CD8⁺ T regulatory cells are selectively impaired. Here, we review current evidence of how the process of immunosenescence impacts the risk for GCA and how fundamental differences in the age of the immune system translate into differences in the granulomatous immunopathology of TAK versus GCA.

Antiphospholipid syndrome (APS) is an autoimmune thrombophilia propelled by circulating antiphospholipid antibodies that herald vascular thrombosis and obstetrical complications. Antiphospholipid antibodies recognize phospholipids and phospholipid-binding proteins and are not only markers of disease but also key drivers of APS pathophysiology. Thrombotic events in APS can be attributed to various conspirators including activated endothelial cells, platelets, and myeloid-lineage cells, as well as derangements in coagulation and fibrinolytic systems. Furthermore, recent work has especially highlighted the role of neutrophil extracellular traps (NETs) and the complement system in APS thrombosis. Beyond acute thrombosis, patients with APS can also develop an occlusive vasculopathy, a long-term consequence of APS characterized by cell proliferation and infiltration that progressively expands the intima and leads to organ damage. This review will highlight known pathogenic factors in APS and will also briefly discuss similarities between APS and the thrombophilic coagulopathy of COVID-19.

Deficiency of adenosine deaminase 2 (DADA2) was first described as a monogenic form of systemic vasculitis that closely resembles polyarteritis nodosa (PAN). The phenotypic spectrum of DADA2 has vastly expanded in recent years and now includes pure red cell aplasia, bone marrow failure syndrome, lymphoproliferative disease, and humoral immunodeficiency. Vasculitis remains the most common presentation of DADA2, and treatment with tumor necrosis factor inhibitors (TNFi) has shown remarkable efficacy in preventing stroke and ameliorating features of systemic inflammation. The precise function of ADA2 has not been elucidated, and how absence of ADA2 ignites inflammation is an active area of research. In this review, we will discuss the current understanding of DADA2 from research and clinical perspectives. We will evaluate several proposed functions of ADA2, including polarization of monocyte phenotype, regulation of neutrophil extracellular trap formation, and modulation of innate immunity. We will also review the role of inflammatory cytokines including TNF and type I interferons. Lastly, we will provide future perspectives on understanding the phenotypic heterogeneity of DADA2 and discuss potential treatment options.

Atherosclerosis is a chronic inflammatory disease of the vascular system that is characterized by the deposition of modified lipoproteins, accumulation of immune cells, and formation of fibrous tissue within the vessel wall. The disease occurs in vessels throughout the body and affects the functions of almost all organs including the lymphoid system, bone marrow, heart, brain, pancreas, adipose tissue, liver, kidneys, and gastrointestinal tract. Atherosclerosis and associated factors influence these tissues via the modulation of local vascular functions, induction of cholesterol-associated pathologies, and regulation of local immune responses. In this review, we discuss how atherosclerosis interferers with functions of different organs via several common pathways and how the disturbance of immunity in atherosclerosis can result in disease-provoking dysfunctions in multiple tissues. Our growing appreciation of the implication of atherosclerosis and associated microenvironmental conditions in the multi-organ pathology promises to influence our understanding of CVD-associated disease pathologies and to provide new therapeutic opportunities.