Page 255 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

Cryoglobulinemic Vasculitis 229

Etiopathogenesis

The etiopathogenesis and triggering factors of CV and MCs are depicted in Figures 1 and
2. Vascular deposition of circulating IC, cryoglobulins and complement mediated by humoral
and local factors, affects small vessels, predominantly arterioles, capillaries, and venules
similar to Henoch-Schonlein purpura, another IC type of SVV with variable systemic organ
involvement [1-5]. Mild to moderate chronic hepatitis is related in up to two-thirds of affected
patients with CV [1-4, 9] suggesting a pathogenic role for hepatotropic viruses. Since
suggested more than four decades ago, hepatitis B virus (HBV) is a possible causative factor
in <5% of patients, while HCV is considered the main pathogenic agent in CV [1, 4, 5]. First
proposed by two independent groups who recognized the increased prevalence of serum anti-
HCV antibodies in CV patients relative to the general population [10, 11], a causative link
between HCV and CV was later established when the presence of HCV RNA was detected by
polymerase chain reaction (PCR) in 86% of patients with CV [7]. The causative role of HCV
in CV is apparent in up to 95% of patients among cohorts of diverse geographical derivation
[1, 4-6, 9]. In consideration of the striking association of HCV with CV, EMC occurs in a
minority of patients [1, 4]. The clinical features and prognosis of CV are linked to the natural
history of chronic HCV infection with different CV phenotypes believed to be the result of
contributory genetic and environmental cofactors which hitherto remain unknown [1, 4, 12].
The role of HCV in autoimmunity has be ascribed to viral lymphotropism [1, 4, 5, 12]
wherein the HCV, which lacks the ability to integrate into the host genome due to absence of
reverse transcriptase activity, chronically stimulates the immune system leading to
autoimmune phenomena. The proposed etiopathogenesis (Figure 2) is connected to HCV-
related epitopes, autoantigens, and molecular mimicry-related mechanisms such as the
association with the anti-GOR autoantibody, as well as the binding of HCV to host low-
density lipoprotein (LDL), specific antiviral IgG and IgM, RF and cryoglobulins, and
monoclonal RF bearing B-cells that express the WA cross-idiotype. Collectively, these
immunological phenomena are the cause and the consequence of chronic stimulation of B-
lymphocytes with expansion of B-cell subpopulations. The mucosa-associated lymphoid
tissue (MALT) related lymphoma of the stomach related to gastrointestinal Helicobacter (H.)
pylori infection [1, 4, 12], has an analogous multistep and multifactorial etiopathogenesis.

The interaction between the HCV E2 envelope protein and CD81 molecule, a ubiquitous
tetraspannin present on the surface of B cells, likely represents an important pathogenic step
in the development of HCV-related autoimmune and lymphoproliferative disorders that
results in potent sustained polyclonal stimulation of the B-lymphocytes [1, 4, 12]. The
occurrence of HCV-related autoimmune-lymphoproliferative disorders may also be related to
t(14;18) translocations found in B-cells of HCV-infected patients leading to increased
expression of the Bcl-2 protein with inhibition of apoptosis and abnormally prolonged B-cell
survival [1, 4, 12, 13]. Apart from cryoglobulin production with or without overt CV, HCV-
driven lymphoproliferation could explain the pathogenic role of HCV infection in idiopathic
B cell lymphoma (1, 4). Epidemiological and laboratory studies have confirmed this
association in geographical areas where both HCV-associated CV and lymphoproliferative
disorders occur [1, 4, 12].

The etiopathogenesis of HCV-negative CV remains a challenge to explain apart from
concurrent infectious processes including HBV and concomitant autoimmune rheumatologic
and lymphoproliferative disorders (Figure 1).

Complimentary Contributor Copy