Metal as an Antigen?

Who’s scared of a little metal? YOU SHOULD BE. With an atomic number of 4 and an atomic weight of 9, the lightest metal on the periodic table is beryllium (Be). Beryllium’s properties make it very valuable. It is used in many industries including aerospace, defense and ceramics. It is also used in everyday objects such as light fixtures, golf clubs and electronics. Even though beryllium has properties such as conductance and weight that make it advantageous, there is a flip side to the coin. Beryllium, in the form of particulate dust, can and does get inhaled by those who mine, machine and form the metal into objects used everyday. This inhalation causes a disease in the susceptible known as berylliosis or Chronic Beryllium Disease.

Chronic Beryllium Disease (CBD) is a CD4 (helper) T cell mediated disease. In this affliction, inhaled particles of beryllium are taken up by alveolar macrophages (those in the lung). Up to 14% of this endocytized beryllium may be presented (unpublished results) in the contest of specific MHC class II on the macrophage to beryllium responsive helper T cells. This presentation causes a signaling cascade through the T cell receptor (TCR) and leads to events including macrophage cell death by apoptosis, T cell expansion, T cell pro-inflammatory cytokine release and granuloma formation in the lungs. These granulomas cause a slew of problems that can never be fully resolved.

Presentation of beryllium is performed mostly by a subset of MHC class II known as HLA-DP. Remember that HLA-DP, HLA-DR and HLA-DQ are the three HLA in the human genome. Within the HLA-DP there are subsets and the one most responsible for CBD is HLA-DP0201. In a paper by Richeldi et al. they found that 83% of subjects suffering form CBD were HLA-DP0201, compared to 30% of the unaffected population.

However, there are also other HLA including some DR and DQ subtypes that are found in CBD patients. After several years of work researchers have found that all of the HLA types (DR, DQ or DP) that confer susceptibility to beryllium have a glutamic acid corresponding to position 69 (Glu69) of the HLA-DP beta-pleated sheet. Recently, researchers at University of Colorado Denver have shown that substitution of amino acids in the HLA-DP0201 abrogates the T cell response to beryllium.

Performing a series of experiments involving amino acid substitutions, researchers were able to observe that replacement of certain amino acids affected the T cells beryllium specific response. The substitution of the glutamic acid at position 69 of the beta chain with the uncharged amino acid alanine either interferes with T cell recognition or HLA-DP0201 presentation. Either way, T cell response was totally abolished. This abolishment of beryllium specific T cell response was also observed during substitution of several other beta chain amino acids that have been modeled to have interaction with the TCR of beryllium responsive T cells. Since the T cell can not respond to the beryllium (either because the TCR can not interact with the MHC or the MHC has been changed so that it cannot present beryllium to the TCR) it will not make pro-inflammatory cytokines or direct the alveolar macrophages to wall off the insoluble beryllium in a granuloma.

This study has highlighted the importance of the delicate balance between the MHC and the TCR in interactions to develop disease. If a particular MHC cannot present a particular antigen there can be no disease. Also, if the responsive TCR cannot bind the MHC with a particular antigen, there can be no disease.

Mutagenesis of beryllium-specific TCRs suggests an unusual binding topology for antigen recognition.

Bowerman NA, Falta MT, Mack DG, Kappler JW, Fontenot AP.

J Immunol. 2011 Oct 1;187(7):3694-703. Epub 2011 Aug 26.