From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Dendritic Cells and HIV
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6631
Organization: unspecified
Date: Mon, 14 Dec 92 08:03:24 PST

                    NEW STUDIES ON LC/DC AND DNCB

Langerhans and dendritic cells are alive and well and still proving to 
be the key cells in the immunopathogenesis of AIDS. Langhoff's article 
is well worth reading as he also mentions follicular dendritic cells and 
the lymph node effect mentioned in Fauci's forthcoming article in the 
New England Journal of Medicine.

Cumberbatch's article supports the idea the DNCB is a pure Th1 activator 
and does not cause immediate hypersensitivity problems as does most of 
the other biological response modifiers (BRM). The activation by Th1 of 
Ig2a (in mice) is very interesting. It appears to act against the 
exogenous particles of intracellular pathogens thus causing their 
destruction probably by opsonization resulting in phagocytosis or 
chemolysis. In mice, the IgG types are IgG1, IgG2a, IgG2b, and IgG3; in 
humans it is IgG1, IgG2, IgG3, and IgG4. They have not yet determined 
which of the IgG isotypes is activated during the Th1 response in 
humans.
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Langhoff E; Haseltine W. Infection Of Accessory Dendritic Cells By Human 
Immunodeficiency Virus Type-1. Journal Of Investigative Dermatology, 
1992 Nov, V99 N5:S89-S94.

Abstract: Many details of the pathogenesis of the human immunodeficiency 
virus type 1 remain to be elucidated. Details of how the virus gains 
entry via the mucosal surface upon sexual contract or during breast 
feeding remain obscure. The means by which the infection travels 
throughout the body as well as the nature of the major reservoirs of 
virus infection remains, for the most part, unknown. 
   Recent studies raise the possibility that cells of the 
Langerhans/dendritic lineage play a central role in human 
immunodeficiency virus (HIV-1) infection and pathogenesis. It has been 
known for several years that veiled dendritic cells in the circulation 
as well as skin Langerhans are infected in people with prolonged HIV-1 
infections. More recently it has been found that a large burden of 
viral DNA sequences if found, not only in the circulating T-cell 
population, but also in a population that is defined as a non-T, non-B, 
non-monocyte/macrophage population rich in T-helper dendritic cells.
   Detailed analysis of infection of primary Blaud-derived T-helper 
dendritic cells by HIV-1 shows that such cells are the most susceptible 
cells in the blood to infection by this virus. The cells also produce 
much more virus per cell than do purified populations of other blood 
mononuclear cells. Moreover, primed blood-derived T-helper dendritic 
cells are not killed by infection by HIV-1. These cells are susceptible 
to lymphotropic, monocyte tropic, and primary isolates of HIV-1.
   The sensitivity of primary blood-derived T-helper dendritic cells to 
infection by HIV-1 has been shown to be attributed to rapid uptake of 
virus particles as well as rapid synthesis of viral DNA. Subsequent 
steps of virus replication also occur more rapidly and more efficiently 
in populations of primary blood-derived T-helper dendritic cells than 
they do in purified preparations of blood-derived T cells and 
monocytes/macrophages.
   Studies with primates using the simian immunodeficiency virus (SIV) 
show that dendritic cells at the surface of sexual mucosa are rapidly 
infected upon exposure to high concentrations of the virus. SIV is also 
produced in abundance in Langerhans cells located at the surface of the 
sexual mucosa in animals infected for prolonged periods of time.
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Cumberbatch M; Gould S; Peters S; Basketter D; Dearman; Kimber I;
Langerhans Cells, Antigen Presentation, And The Diversity Of Responses 
To Chemical Allergens.
Journal Of Investigative Dermatology, 1992 Nov, V99 N5:S107-S108.

Abstract: Respiratory and contact chemical allergens provoke differential 
immune responses in mice, stimulating preferentially T helper-2 (TH2) 
and TH1 cells respectively. In an attempt to discover whether such 
differences are effected at the level of antigen handling and 
presentation we have examined the effect of topical exposure to 
trimellitic anhydride (TMA), a respirator allergen, and 
2,4-dinitrochlorobenzene (DNCB), a contact allergen, on Langerhans 
cell (LC) MHC class II (Ia) expression. Neither chemical caused a 
significant change in LC size. As measured by analytical flow cytometry, 
exposure to DNCB resulted in a tide-dependent increase in LC Ia 
expression that exceed 160% of control values within 24 h. Exposure to 
concentrations of TMA that caused an equivalent activation of draining 
lymph nodes failed to affect Ia expression by LC. Application of sodium 
lauryl sulfate at concentrations that caused edema also failed to 
influence LC Ia. These data demonstrate that TMA and DNCB exert 
differential effects on epidermal LC, possibly indicative of differences 
in antigen handling.

Page 107S: Thus, for example, despite evidence for occupation exposure 
and for the development of occupational allergic contact dermatitis, 
2,4-dinitrochlorobenzene (DNCB) does not induce respiratory 
hypersensitivity.

We hypothesized that the failure of DNCB to induce IgE antibody was 
attributable to a preferential activation of TH1 cells and, conversely, 
that a selective activation of TH2 cells by TMA would be consistent with 
the ability of this chemical to provide IgE responses and to cause 
respiratory hypersensitivity. Support for this hypothesis derived from 
analysis of the isotype distribution of IgG anti-hapten antibody induced 
following exposure to these chemical. IFN-gamma, but not TH2 cytokines 
promotes production of the IgG2a isotype. We found that DNCB resulted in 
a substantially stronger IgG2a that IgG2b antibody response. In 
contract, exposure to TMA provoked significantly less IgG2a than IgG2b 
antibody. Subsequent investigations with other chemicals have confirmed 
that respiratory allergens induce immune responses characteristic of the 
selective activation of TH2 cells, whereas contact allergens that 
apparently lack the potential for respiratory sensitization stimulate 
preferentially TH1-type responses.
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Newsgroups: sci.med.aids