Expression of macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response

Abstract

The in vivo response of the immune system after HIV infection in regard to cytokine production and C-C chemokine synthesis is not well known. Here we have analysed cytokine and chemokine mRNA production in lymph nodes with follicular hyperplasia (FHLN) of HIV-infected patients by in situ hybridization using anti-sense mRNA probes. The synthesis of mRNAs for interferon-gamma (IFN-gamma), IL-12p35, IL-12p40, IL-4, and for the C-C chemokines RANTES, MIP-1alpha, and MIP-1beta was compared with that of lymph nodes from non-infected individuals to define HIV-specific events. Only few cells expressing IFN-gamma, RANTES, MIP-1alpha, and MIP-1beta mRNAs were detectable in the T-dependent area of lymph nodes from HIV-negatives. In contrast, in FHLN from HIV+ patients a high number of IFN-gamma, RANTES, MIP-1alpha, and MIP-1beta mRNA-containing cells were detectable. Remarkably, only single individual IL-12p35 mRNA-producing cells were present in the T-dependent area from both HIV+ and HIV lymph nodes. Furthermore, the low number of IL-12p40 mRNA-expressing cells did not differ between HIV+ and HIV- lymph nodes. This indicates that IFN-gamma is expressed independently of IL-12, possibly by a direct T cell-mediated reaction. IL-4 mRNA-producing cells were hardly detectable in infected and control lymph nodes. The same findings were made in a limited number of samples from patients with advanced disease. Thus, these results demonstrate that a high IFN-gamma production is accompanied by a strong expression of MIP-1alpha, MIP-1beta, and RANTES in the lymph node after HIV infection. This favours the idea that a Th1-type immune response correlates with a preferential production of C-C chemokines in FHLN of HIV+ patients.

Fig. 1

IFN-γ mRNA production in HIV⁻ and HIV⁺ lymph nodes. Lymph nodes with follicular hyperplasia (FHLN) of HIV⁺ individuals and lymph nodes from HIV⁻ persons were hybridized with an IFN-γ-specific antisense cRNA probe. (A) Lymph node section from a HIV⁻ individual. (B) Lymph node section from a Mycobacterium tuberculosis-infected but HIV⁻ patient. (C) Lymph node section from a HIV⁺ person (Mag. × 50).

Fig. 2

Identification of the cell types producing IFN-γ and MIP-1α mRNA. Lymph node sections were subsequently labelled with anti-CD4 (A, C), anti-CD8 (B, D), and anti-CD68 (E), respectively, and hybridized with an IFN-γ (A, B) or MIP-1α (C, D, E)-specific riboprobe. Double-positive cells were marked with an arrow. (Mag. A × 168, B–E × 100.)

Fig. 3

MIP-1α, MIP-1β, and RANTES mRNA production in HIV⁻ and HIV⁺ lymph nodes. Lymph nodes with follicular hyperplasia (FHLN) from HIV⁺ individuals and lymph nodes from HIV⁻ persons were hybridized with MIP-1α (A–C)-, MIP-1β (D–F)-, and RANTES (G–I)-specific antisense cRNA probes. (A,D,G) Lymph node sections from an HIV⁻ individual. (B,E,H) Germinal centre in the lymph node from an HIV⁺ patient. (C,F,I) T-dependent area in the lymph node from an HIV⁺ person. (Mag. × 50.)