Susceptibility to tuberculosis has been known for years to be strongly influenced by human genetic factors. However, only a few distinct genetic variants so far have been reported to be associated with susceptibility or resistance to the disease, and these variants have been found to exert moderate effects only.1
Recently, the mouse gene Ipr1
(intracellular pathogen resistance‐1) on the locus sst1
(super‐susceptibility to tuberculosis 1) has been shown to essentially contribute to innate immunity in a murine model of Mycobacterium tuberculosis
Upregulation of Ipr1
after infection occurs in macrophages from sst1
resistant mice, but not in those from susceptible mice, and expression of an Ipr1
transgene construct in macrophages from susceptible animals resulted in the control of mycobacterial replication and eventually induced death of infected cells. Thus, Ipr1
might play an important role in preventing tuberculosis by mediating control of M tuberculosis
within its prime target cell, the macrophage.
The human homologue of Ipr1
037 bp on 2q37.1; MIM
The corresponding protein, SP110 (nuclear body protein SP110; also known as transcriptional coactivator SP110 or interferon induced protein 41/75), shows 41% identity to the murine protein encoded by Ipr1
. Three transcripts designated Sp110a
, and ‐c
have been identified and contain 18, 15, and 19 exons, respectively. The first exon of all transcripts is invariably untranslated. Exons 15a and 15b define the alternate transcripts Sp110a
, and Sp110c
contains exon 15a and an additional short exon 17.
SP110 is a component of the nuclear body, a multi‐protein complex assumed to participate in the regulation of gene transcription. SP110 has considerable homology with the nuclear body proteins SP100 and SP140. After induction by interferon‐α and interferon‐γ, SP110 is preferentially expressed in leukocytes and spleen cells, but also at lower levels in many other tissues.3,4
SP110 proteins contain structural motifs which suggest participation in protein‐protein interactions, such as the N‐terminal SP100‐like domain.5,6
The conserved SAND domain (Sp100, AIRE‐1, NucP41/75, and DEAF‐1/suppressin) is most likely involved in transcriptional regulation through DNA binding.7,8
In addition, the proteins are characterised by nuclear localisation signal sequences and the nuclear receptor binding motif LXXLL (leucine/any two amino acids/leucine/leucine). SP110a differs from SP110b in exhibiting a C‐terminal bromodomain that enhances transcription of genes with retinoic acid response elements.3,9
The absence of the bromodomain in SP110b is thought to cause suppression of transcription of these genes.
A number of single nucleotide polymorphisms (SNPs) have been identified in the Sp110
). Several of the variants have been claimed to be associated with distinct clinical phenotypes of hepatitis C.10
Furthermore, SP110b has been reported to interact with hepatitis C core and Epstein‐Barr virus SM proteins.9,11
If Ipr1 is essential in the control of M tuberculosis and of apoptosis of infected cells in mice, Sp110 might also be relevant to the course of human M tuberculosis infection. Therefore, we have tested whether variants of Sp110 are associated with susceptibility or resistance to human tuberculosis. Since the individual reactivity to intradermal purified protein derivative (tuberculin, PPD) M tuberculosis antigens reflects the extent of the T cell immune response and is grouped into PPD positivity and PPD negativity, the control group of our association study was stratified according to the different sizes of the skin reaction measured after tuberculin application.