From: bigoldberg@igc.apc.org (Billi Goldberg)
Newsgroups: sci.med.aids
Subject: HIV and B-cell Dysregulation
Date: 4 Jan 93 14:33:22 GMT
Organization: unspecified
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6709


               HIV INFECTION AND B-CELL DYSFUNCTION
                         Billi Goldberg

In a previous post, I stated that HIV+ individuals still had B cell 
memory and were able to fight off pathogens which depended on clearance 
by the Th2 or antibody response. An individual sent me an E-mail 
reminding me that there were B-cell dysregulation such as increased B-
cell activation and immaturity, and hypergammaglobulinemia, and abnormal 
cytokine levels. This dysregulation apparently starts during early 
asymptomatic infection. Of course, he was right, but I was only looking 
at disease control. 

While researching Th1/Th2, I ran across the following article by 
Kullberg that shows how Schistosoma helminth infection can cause 
hypergammaglobulinemia when the immune system is fighting off the 
infection with the antibody system. This effect, controlled by increased 
cytokine production of IL-6 and IL-10, shuts down the Th1 or cell 
mediated immune response. Perhaps, the hypergammaglobulinemia in early 
HIV infection shuts down the ability of the Th1 to clear HIV infection.

If this is so, it once again supports the need for effective immune 
modulation in HIV+ individuals such as caused by regular use of DNCB 
which initiates strong cell mediated immune responses and shuts down the 
antibody responses. 

It is extremely important that more research is accomplished in the area 
of early and late immune boosting in HIV+ individuals by use of potent 
and specific delayed type hpersensitivity (Th1, CMI) initiators.              
                                          
======================================================================= 
Kullberg MC; Pearce EJ; Hieny SE; Sher A; Berzofsky JA. Infection with 
Schistosoma mansoni alters Th1/Th2 cytokine responses to a non-parasite 
antigen. Journal of Immunology, 1992 May 15, 148(10):3264-70. 

Abstract: Schistosoma mansoni infection in the mouse has been shown to 
be accompanied by a down-regulation in parasite-Ag- and mitogen-induced 
Th1 cytokine secretion (IL-2 and IFN-gamma) with a simultaneous increase 
in the production of Th2 cytokines (IL-4, IL-5, and IL-10), suggesting a 
generalized imbalance in lymphocyte function. In the present study, we 
examined whether infection with S. mansoni would also influence the 
character of immune responses to a non-parasite Ag, sperm whale 
myoglobin (SwMb). When spleen cells (SC) from schistosome-infected SwMb-
immunized animals were stimulated with SwMb, their production of IL-2 
and IFN-gamma per CD4+ cell was found to be significantly reduced (by 
45% and 59%, respectively) compared with the responses observed in 
immunized uninfected animals. Moreover, SwMb-induced secretion of IL-4 
per CD4+ cell was increased threefold in SC cultures from infected mice. 
No myoglobin-induced IL-5 was detected in the same cultures. Addition to 
SC cultures of a neutralizing mAb specific for IL-10 partly restored the 
suppressed IFN-gamma response to SwMb seen in infected mice, suggesting 
a role for IL-10 in the observed down-regulation. S. mansoni-infected 
mice also showed an impaired antibody response to SwMb, with levels 
ranging from 10% to 27% of those observed in uninfected mice, although 
no differences in IgG isotype were evident. Taken together, these 
results suggest that infection with S. mansoni induces a down-regulation 
of Th1 responses and elevation of Th2 responses to unrelated foreign 
immunogens as well as to parasite Ag themselves. One implication of 
these findings is that helminth-infected individuals may have altered 
cell-mediated immune function to other microbial agents. 
======================================================================= 
Breen EC; Rezai AR; Nakajima K; Beall GN; Mitsuyasu RT; Hirano T; 
Kishimoto T; Martinez-Maza O. Infection with HIV is associated with 
elevated IL-6 levels and production. Journal of Immunology, 1990 Jan 15, 
144(2):480-4.   

Abstract: Polyclonal B cell activation is commonly observed in AIDS and 
in infection with HIV. Because IL-6 (B cell stimulatory factor 2) plays 
an essential role in the differentiation of activated B cells to 
Ig-secreting cells, and because IL-6 production is induced by exposure 
of human PBMC to HIV, we measured the level of circulating plasma IL-6,
spontaneously-produced IL-6, and IL-6 mRNA in HIV-infected donors and in
healthy control donors. Elevated levels of plasma IL-6 and IL-6 mRNA 
were detected in HIV-infected donors. PBMC isolated from the peripheral
circulation of HIV-infected donors, and cultured without added exogenous
activators of IL-6 production, produced markedly elevated amounts of 
IL-6 when compared with cells isolated from healthy donors. 
Interestingly, levels of an acute-phase protein, which is known to be 
induced by IL-6, was also increased in HIV-infected donors. These 
results demonstrate that elevated levels of IL-6 are associated with 
HIV-infection, and suggest that IL-6 over-production may contribute to 
the polyclonal B cell activation seen in AIDS and HIV infection.
Newsgroups: sci.med.aids