The Kunkel legacy and hepatitis C virus infection.

In commemoration of Henry Kunkel's 100th birthday, the effect of his legacy on the investigation of hepatitis C virus is recounted. The delineation of a major cross-idiotype (WA) among patients with essential mixed cryoglobulinemia led to the discovery that HCV was the etiologic agent for this disease. Studies of the cryoglobulins led to the discovery that WA RF reacted specifically with HCV-VLDL like particles that on electronmicroscopy and binding studies appeared to be the virion within a lipid shell. This particle mediates cell entry via LDLr and may serve to avoid the immune response by masking the virion. In addition, the WA B cell may be a prognostic marker for cutaneous vasculitis and B cell malignancy in HCV-infected patients. In commemoration of Henry Kunkel's 100th birthday, this is an account of how his legacy had a role in the investigation of hepatitis C virus (HCV) infection. There is a bit of a historical basis for the legacy of this great immunologist having a role in virology. He began his research career studying hepatitis. Later he worked with HCV in his studies of mixed cryoglobulins although he didn't know it at the time. There may also have been a Kunkel historical basis for why he accepted me as fellow in his laboratory considering that my credentials paled in comparison with those of the fellows and PhD students in his laboratory. Like Henry I was drafted into the Navy following my internship, I had had minimal research experience in medical school and only one minor publication, and I had a passion for clinical investigation. It may have been fortuitous that while on active duty at the Bayonne NJ Naval Base I visited Henry Kunkel in my Navy uniform and told him I was interested in studying SLE. I did not know at the time the dramatic role the Navy had played in his career or that one of his major training goals was to teach MDs to use clinical observation as a focus for delineating disease mechanisms in the laboratory. When I started work in the laboratory on discharge from the Navy, the first thing he told me was that it took five years to make a clinical investigator so I might as well get a Rockefeller University PhD while working in his laboratory. I was sure I would leave the laboratory after two years so I declined his offer. I did not leave until six years later!

Detection of WA B cells in hepatitis C virus infection: a potential prognostic marker for cryoglobulinemic vasculitis and B cell malignancies.

OBJECTIVE: An uncommon manifestation of hepatitis C virus (HCV) infection is systemic vasculitis associated with type II cryoglobulinemia (cryoglobulinemic vasculitis), a proliferative B cell disorder that transforms into B cell malignancy in 5-10% of patients. The monoclonal rheumatoid factors (mRF) that bear the WA cross-idiotype (Xid) are responsible for most cases of cryoglobulinemic vasculitis in patients with HCV infection. The purpose of this study was to determine whether WA B cells can be detected in asymptomatic patients with HCV infection, using sequence analysis of B cell clonal expansions (BCEs) to identify the WA Xid. METHODS: Asymptomatic patients with HCV infection and those without HCV infection as well as respective control patients with cryoglobulinemic vasculitis, whose serum was either negative or positive for WA mRF, were studied. BCEs were isolated in the patients' blood, and WA BCEs were identified by sequencing analysis. RESULTS: BCEs were detected in all control patients with cryoglobulinemic vasculitis, but only control patients with HCV infection had WA BCEs. None of the 33 asymptomatic patients without HCV infection had a BCE. WA BCEs were detected in 4 (7.4%) of 55 asymptomatic patients with HCV infection, in none of 14 patients with HCV infection and type III cryoglobulinemia, and in 5 (13.5%) of 37 patients with HCV infection and serum RF positivity. One patient with a WA BCE had splenic lymphoma markers and villous lymphocytes, and the villous lymphocytes were found to be WA B cells. CONCLUSION: By identification of the WA Xid, WA B cells can be detected in asymptomatic HCV-infected patients. WA B cells in asymptomatic patients with HCV infection may be a marker for the development of cryoglobulinemic vasculitis and associated B cell malignancies. The results of this study provide a basis for the development of the first practical clinical application of cross-idiotype analysis.

Observations on cryoglobulin testing: II. The association of oligoclonal mixed cryoglobulinemia with cirrhosis in patients infected with hepatitis C virus.

OBJECTIVE: To determine whether a mixed cryoglobulin type correlated with cirrhosis in patients infected with hepatitis C virus (HCV). METHODS: We investigated the results of mixed cryoglobulin tests performed in the clinical laboratory on patients with and without HCV infection. RESULTS: A higher prevalence of oligoclonal cryoglobulins designated Type IIa was present in HCV-infected patients with cirrhosis than in those without cirrhosis. CONCLUSION: An association of Type IIa cryoglobulins with cirrhosis in HCV-infected patients has not previously been reported.

Observations on cryoglobulin testing: I. The association of cryoglobulins containing rheumatoid factors with manifestation of cryoglobulinemic vasculitis.

OBJECTIVE: To investigate the results of mixed cryoglobulin tests performed on patients with and without hepatitis C virus (HCV) infection, to determine whether type II cryoglobulins containing rheumatoid factor (Type II-RF) were associated with cryoglobulinemic vasculitis. METHODS: The cryoglobulin test protocol differed from the routine protocol. In addition to determination of both cryoglobulin concentration and immunoglobulin composition, the presence or absence of RF concentrated in the cryoglobulins was determined. RESULTS: A qualitative and quantitative association of Type II-RF cryoglobulins with cryoglobulinemic vasculitis was present among HCV-infected patients. CONCLUSION: Detection and quantification of Type II-RF may enhance clinical monitoring of cryoglobulinemic vasculitis in HCV-infected patients.

Prevalence of Hepatitis C virus infection in a sample of homeless veterans.

OBJECTIVE: This study measures the prevalence of Hepatitis C Virus (HCV) infection in a sample of homeless veterans treated in a Domiciliary Care for Homeless Veterans (DCHV) program in Massachusetts. We also examine risk factors and correlates for HCV infection, including substance abuse and service in Vietnam. METHODS: Patients admitted to the DCHV program over a 5-year period (n=418) were systematically tested for HCV infection. Blood test data were merged with standardized data collection forms to assess socio-demographic characteristics, military history, and medical and psychiatric history. RESULTS: The overall prevalence rate of HCV infection was 44.02%, a rate more than ten times higher than the national rate for men age 20-59 and more than twice as high as other VA patient samples. Adjusting for age, significant risk factors in this sample included a history of substance abuse (OR=6.86, p<0.0001) and service during the Vietnam era (OR=4.66, p=0.01). Comparisons of the tested sample with other homeless veterans treated in 34 similar programs nationally indicated that this sample did not significantly differ from other treated homeless veterans with respect to demographics or HCV risk factors. CONCLUSIONS: We found a high prevalence of HCV infection in this population that is not likely to be geographically unique, and may indicate particularly high risk for homeless men. Substance abuse is the most important risk factor, and we hypothesize that the effect of Vietnam-era service is a proxy for unreported drug use. We advise an increase in screening and education for all homeless populations, particularly those with a history of injection drug use. Public systems of care, including the VA, should expect increasing costs of care related to HCV infection as prevalent cases develop serious medical sequelae of HCV infection.

Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia.

A patient with type II cryoglobulinemic vasculitis and hepatitis C virus (HCV) infection presented with a leukemiclike proliferation of B cells bearing marginal zone B-cell phenotypic markers. A partial trisomy 3 (bands 3q11-29) and overexpression of Bcl-2 without t(14;18) translocation was detected in the monoclonal B cells that were classic rheumatoid factor-producing B cells bearing the WA cross-idiotype. Treatment with interferon-alpha produced a complete clinical remission and synchronous marked decreases in viremia and monoclonal B-cell prevalence. This is the first report of partial trisomy 3 and Bcl-2 overexpression in type II cryoglobulinemic vasculitis associated with HCV infection. Further studies of HCV-infected patients with and without type II cryoglobulinemia are required to determine the prevalence and possible physiologic and/or pathophysiologic significance of these findings.