INTERACTION OF HLA MOLECULES WITH NON-IMMUNOLOGICAL LIGANDS AS AN EXPLANATION OF HLA AND DISEASE ASSOCIATIONS

doi:10.1016/S0140-6736(76)91796-7

The Lancet

Volume 308, Issue 7985, 11 September 1976, Pages 547-549

https://doi.org/10.1016/S0140-6736(76)91796-7 Get rights and content

Abstract

It is postulated that alloantigens (HLA in particular) may interfere with ligand/ receptor interactions not directly involved in immune reactions. This interference may be regarded as a side-effect of the creation of new mutant HLA alleles which are maintained in the population for other reasons. As an example, it is suggested that some HLA molecules may have structures resembling those on receptors for certain hormones which could cause competition between HLA and receptor molecules for the hormone. Facilitation of ligand/receptor interaction may also be envisaged. Such interactions could under certain conditions lead to disease and might explain some associations between HLA and non-immunological diseases (e.g., manic-depressive disease and hæmachromatosis).

References (27)

H.O. McDevitt et al.
Lancet
(1974)
P.C. Doherty et al.
Lancet
(1975)
J.C. Ellory et al.
Immunochem.
(1973)
Transplantn Rev.
(1975)
J. Klein
Biology of the Mouse Histocompatibility-2 Complex
(1975)
R. Coppellini
R. Thorsby
Transplantn Rev.
(1974)
A. Svejgaard et al.
Monogr. hum. Genet.
(1975)
G.D. Snell
Folia biol., Praha
(1968)
W.F. Bodmer
Nature
(1972)

A. Svejgaard et al.

Trans plantn Rev.

(1975)

Good, R. A. Personal...

O. Ringden et al.

Scand. J. Immun.

(1975)

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Citation Excerpt :
Hetero-associations of MHCI with the MHCII, ICAM-1, tetraspan molecules, transferrin receptor, and the interleukin-2 and -15 receptor subunits (α, β, γc) have been described on the surface of several cancerous cell lines of lymphoid (HUT-102B2, Kit-225 K6 T-lymphoblasts, and JY B-lymphoblast), colorectal (LS174 T) and uveal origin (OCM-1, OCM-3), as well as on the CD4+ T-cells from the peripheral blood and lymph nodes of patients in colorectal cancer and Crohn’s disease [1–7]. Although, the above observations are well described by the current concept of membrane organization according to which the lipid-rafts play a fundamental role in holding together the receptor clusters, the specific role for the core element MHCI and MHCII molecules in these clusters has not been clarified yet („MHC enigma”) [8–13]. In addition to their conventional roles in immune-recognition, a passive role in stabilising lipid rafts, as well as a „non-classical” role in signal-transduction (with signal-messengers such as ZAP70, p56lck, Tyk2, PI3K) aiming at modifying signaling thresholds and ensuring signal amplification – e.g. through increasing the effective binding surface of nearby receptors – can be assumed [14–19].
Highly conserved 2D receptor clusters (membrane rafts) of immunological signaling molecules with MHCI and MHCII antigens as their cores have been observed in the past on the surface of T- and B-cell lines of lymphoid origin, as well as on cells from patients with colon tumor and Crohn’s disease. Conservativity is related to the ever presence of MHCI molecules. Although they are suspected to play a role in maintaining these clusters and facilitating transmembrane signaling, their exact role has been left largely enigmatic. Here we are suggesting stochastic resonance (SR), or “noise-assisted signal detection”, as a general organizing principle for transmembrane signaling events evoked by processes like immune recognition and cytokine binding taking place in these clusters. In the conceptual framework of SR, in immune recognition as a prototype of transmembrane signaling, the sea of self-peptide-MHC complexes around a nonself-peptide presenting MHC is conceived as a source of quickly fluctuating unspecific signal (“athermal noise”) serving the extra energy for amplifying the weak sub-threshold specific signal of the nonself-peptide presenting MHC. This same noise is also utilized for a readjustment of the threshold – and also the sensitivity and specificity – of detection by a closed loop feedback control of the TcR-CD8 (CD4) proximity on the detecting T-cell. The weak sub threshold specific signal of nonself-peptide presenting MHC is amplified by the superposing unspecific signals of the neighboring self peptide-MHC complexes towards the T-cell receptor as the detector. Because in a successful detection event both self- and nonself-peptides are detected simultaneously, the principle of coincidence (or lock-in) detection is also realized. The ever presence of MHC islands gets a natural explanation as a source of extra power – in a form of “athermal noise” – needed for coincidence detection and frequency encoding the evoked downstream signals. The effect is quite general, because the actual type of molecules surrounding a chief signaling molecule – like nonself-peptide holding MHC, interleukin-2 and -15 cytokine receptors (IL-2R/15R) – as the fluctuating interaction energy sources is immaterial. The model applies also for other types of signaling, such as those evoked by cytokine binding. The phenomenon of SR can also be interpreted as sampling of a low frequency, specific signal with a high frequency unspecific signal, the “noise”. Recipes for identifying other forms of SR in membrane clusters with biophysical tools are recommended.
Open conformers: the hidden face of MHC-I molecules
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Citation Excerpt :
The view that MHC-I open-up was a mechanism enabling the heavy chain to cis-associate with a new receptor and regulate its function was proposed 20 years ago [18,23,24]. It was preceded by a seminal essay postulating that HLA-I molecules have hidden functions related to the regulation of ligand–receptor interactions that impact on disease development [70], with the subsequent work of Michael Edidin, Lennart Olsson and collaborators moving this field forward [18,23–25,51,71,72]. For many years, the cis-associations between MHC-I molecules and hormone receptors were puzzling owing to the lack of data on their functional significance [24].
A pool of MHC-I molecules present at the plasma membrane can dissociate from the peptide and/or the light chain, becoming open MHC-I conformers. Whereas peptide-bound MHC-I molecules have an important role in regulating adaptive and innate immune responses, through trans-interactions with T cell and NK cell receptors, the function of the open MHC-I conformers is less clear but seems to be related to their inherent ability to cis-associate, both with themselves and with other receptors. Here, we review data indicating the open MHC-I conformers as regulators of ligand–receptor interactions and discuss the biological implications for immune and non-immune cells. The likelihood that the MHC-I heavy chains have hidden functions that are determined by the amino acid sequence of the α1 and α2 domains are discussed.
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The antigen-presenting role of major histocompatibility complex (MHC) Class I molecules in the activation of appropriately restricted T cells is well documented. Now growing evidence indicates that MHC Class I molecules can, in addition, exert a regulatory effect and influence the resulting immune responses. In this report we show that a monoclonal antibody (mAb) directed against a conserved region of the human leukocyte antigens (HLA)-A, -B, and -C was able to inhibit proliferation of human peripheral blood mononuclear cells induced by the superantigen, Staphylococcus enterotoxin A. While anti-HLA inhibition was associated with a decrease in IL-2 receptor (IL-2R) expression, the addition of exogenous IL-2 did not restore the proliferative response in the presence of anti-HLA mAb. The inhibition of DNA synthesis was also associated with a decrease in the expression of the early activation marker CD69. These results suggest a critical role for HLA Class I molecules in the early events of human lymphocyte activation and proliferation as well as in their expression of the IL-2R.
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Failure to find interference between anti-HLA antibodies and chlorpromazine
1990, Biological Psychiatry
Chlorpromazine has been reported to interfere with the action of alloantibodies directed against HLA-A1. We attempted to replicate this finding using peripheral blood lymphocytes from 3 healthy donors in a complement-mediated lymphocytotoxicity assay. We were unable to find evidence of interference between chlorpromazine and the anti-HLA sera tested. Possible reasons for the difference between our finding and the previous report, as well as the implications for schizophrenia, are discussed.
HLA antigens, epilepsy and cytomegalovirus infection
1988, Brain and Development
Thirty-one epileptic patients, selected from among 900 children with previous febrile convulsions and subsequent epilepsy, were typed for HLA antigens. In 16 of the 31 patients CMV was isolated from the urine shortly after the appearance of spontaneous fits; in the remaining 15 patients the virus was never detected. All the examined children were typed for 14 HLA-A, 23 HLA-B, 7 HLA-C and 9 HLA-DR specificities, and compared with a group of healthy subjects. The HLA-A11 antigen was present in 25% of the children with chronic CMV infection and epilepsy, and absent in patients with epilepsy but without CMV infection (p<0.02). The possibility that the A11 antigen is a marker of the predisposing genes for CMV infection in children with epilepsy following FC is proposed

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HypothesisINTERACTION OF HLA MOLECULES WITH NON-IMMUNOLOGICAL LIGANDS AS AN EXPLANATION OF HLA AND DISEASE ASSOCIATIONS

Abstract

Lancet

Lancet

Immunochem.

Transplantn Rev.

Biology of the Mouse Histocompatibility-2 Complex

Transplantn Rev.

Monogr. hum. Genet.

Folia biol., Praha

Nature

Trans plantn Rev.

Scand. J. Immun.

Hypothesis
INTERACTION OF HLA MOLECULES WITH NON-IMMUNOLOGICAL LIGANDS AS AN EXPLANATION OF HLA AND DISEASE ASSOCIATIONS