Giant cell arteritis (GCA) is an important cause of preventable blindness,

Giant cell arteritis (GCA) is an important cause of preventable blindness, most commonly due to anterior ischemic optic neuropathy. immune privilege of the vessel wall. The artery actively participates in the abnormal immune response through CGS 21680 HCl endogenous CGS 21680 HCl immune sentinels, so-called vascular DCs embedded in the adventitia. Advancing age, the strongest of all risk factors for GCA, likely contributes to the dysfunction of the immune system and the vascular system. Expansion of the therapeutic armamentarium for GCA needs to focus on approaches that mitigate the impact of the aging artery and adapt to the needs of the immunosenescent host. Giant cell arteritis (GCA) is an autoinflammatory and autoimmune syndrome (1). Recognizing and managing GCA remain an ophthalmologic emergency because the disease can quickly progress to irreversible vision loss, dip- lopia, or stroke (2). If the Rabbit Polyclonal to SEC22B. underlying vasculitis is promptly treated, vision loss may be reversible and the fellow eye, also at high risk for involvement, can be protected. The disease process underlying GCA is a granulomatous inflammation, which is typically positioned within the wall layers of medium and large arteries. Granulomatous infiltrates are composed of CD4 T cells and highly activated macrophages, often including multinucleated giant cells. The vascular wall, generally an immune-privileged site, responds to the attack with a response-to-injury program, which cul- minates in hyperplasia of the intimal layer, leading to luminal compromise and vessel occlusion. In the majority of patients with GCA, the arteritis CGS 21680 HCl is associated with a syndrome of systemic inflammation, with constitutional symptoms and results in the well-described laboratory abnormalities, such as elevated acute phase markers (sedimentation rate, C-reactive protein). This systemic component is relatively easy to treat with currently available immunosuppressive regimens. In contrast, the vascular complications of GCA remain a major clinical challenge. Recent data suggest that wall-centered inflammation persists chronically. Luminal stenosis/occlusion results in ischemia, and involvement of different vessels supplying the eye, optic nerve, and brain leads to different ocular findings and patterns of vision loss. Extracranial vessel involvement can cause head- ache, jaw claudication, eye pain, scalp infarction, and other ischemic presentations. GCA aortitis leads to aneurysm formation with the associated risk for dissection and rupture. While formerly suspected to represent a granulomatous reaction to a yet unidentified instigator, CGS 21680 HCl it is now clear that the immunopathogenesis of GCA reaches a much higher degree of complexity. Separable lineages of dysfunctional immune cells have CGS 21680 HCl been implicated in driving the disease, making it highly unlikely that a single etiologic agent induces GCA (3). At least 2 distinct immune processes govern early and late disease, emphasizing the need to search for a variety of inciting events. Probably the most important observation in GCA research has come from the recognition that the blood vessel regulates disease susceptibility and progression through immune-stromal communications. A much improved understanding of the immunopathology of GCA, which has emerged over the last decade, is impacting the diagnostic approach to patients suspected to have GCA or diagnosed with GCA. Immunologic studies suggest a much more chronic course of the disease than previously appreciated (4). Accordingly, current therapeutic strategies, while successful in managing acute disease, need to be adapted to longer term goals. An overriding challenge is the advanced age of the affected patient population. While immune aging emerges as one of the underlying pathogenic principles in conferring risk for GCA, it also restricts the potential use of more aggressive means to immunosuppress vessel-wall centered chronic inflammation. DISEASE RISK FACTORS IN GCA Age By far the strongest risk factor to develop GCA is the age of the patient (Table 1) (5). Individuals younger than 50 years seem to be almost completely protected, whereas the 7th and 8th decade of life are high-risk periods. Exceptions to this rule are patients diagnosed with Takayasu’s arteritis that have a vasculitis similar to GCA. They are typically in the 2nd to 4th decade of life and current diagnostic criteria require that the disease onset before 40 years of age. Similar to fundamental differences in age of onset, the geographic regions of the world with high-risk populations for GCA or Takayasu’s arteritis are almost mutually exclusive, supporting the concept that the 2 2 diseases affect two nonoverlapping host populations and thus must have critical differences in etiology and pathogenesis. TABLE 1 Diseases risk factor in giant cell arteritis Aging leads to a profound remodeling of the immune system with weakening of adaptive immunity because of thymic involution, abating ability to maintain tolerance, and resurgence of less sophisticated innate defense mechanisms (6,7). Also, progressive accumulation of chronic infections reshapes the immune system, detracts from the ability to devote immune responses toward new antigens, and promotes a progressive rearrangement of naive and memory immune cell populations. Whether an aged immune system is more likely to generate.