Sensitisation of Forest workers to the oligosaccharide galactose alpha-1, 3-galactose (alpha-gal) is strongly associated with tick bites but not with evidence of tick borne infections

The authors report on the results of IgE assays for galactose alpha-1, 3-galactose (alpha-gal) among forest workers in the region around Balyostock in North East Poland [1]. The patients were being seen for evaluation of possible tick-borne infections primarily tick-borne encephalitis and Lyme disease. The reason for carrying out assays for IgE to α-gal was because of recognition that in many areas of the world tick bites can induce sensitisation to this oligosaccharide which in turn is associated with an unusual form of delayed allergic reactions to red meat [2]. The results show a significant association between a history of tick bites and IgE to α-gal [3]. In addition, in keeping with previous studies they found no association between evidence of a tick borne infection and positive IgE to α-gal [1,4,5]. Our data on serological evidence of Rickettsial organisms among patients with AGS in two areas of the United States showed a high prevalence of positive sera among patients and controls [6]. The most likely explanation of that result is that the positive serology reflects ‘infection’ with Rickettsia amblyomii which is a common symbiont of the Lone Star tick but is not really a pathogen. What matters here is that none of the published results provide evidence that the pathogens carried by ticks contribute to α-gal sensitisation.

There are several features of the report from Dr. Rutkowski and his colleagues that require comment. In particular, there is now evidence that subjects with sensitisation as judged by IgE ab, but no symptoms are at risk for two distinct clinical complications.

Firstly; most of the allergic or anaphylactic reactions to the monoclonal ab (mAb) cetuximab occur in patients who are sensitised to α-gal, but are not aware of relevant symptoms [7]. Those reactions to cetuximab occur because the mAb is expressed in a mouse cell line (SP2O) which glycosylates the n-79 on the Fab of the heavy chain with α-gal [8]. Significantly there are other medicinal products that carry α-gal including some mAbs and the anti-venom CroFab [9,10]. Secondly: as the authors recognise there is now evidence from the United States and Australia that sensitisation to α-gal is associated with increased prevalence of severe forms of coronary artery disease (CAD) [11,12]. The two studies quoted here used different approaches to study CAD, but in each case it involved high resolution. Thus in Virginia Dr. Taylor used intravascular ultrasound (IVUS), while the data from Dr. Figtree and her colleagues in Sydney used high resolution CT [11,12].

Alpha-gal was first described by Karl Landsteiner as a ‘B-like’ blood group antigen on the red cells of non-primate mammals. He also recognised that this antigen was the target of natural antibodies in the serum of all immunocompetent humans [13]. The importance of this oligosaccharide as a transplantation barrier between mammals such as pigs and primates, was recognised by Uri Galili and others [14]. However, the recent successful short term transplantation of kidneys from α-gal knock out (α-gal-KO) pigs into humans has dramatically confirmed that it is the immune response to this antigen that is responsible for hyper-acute rejection of organs from wild type pigs. The results also support our view that the effect of tick bites on humans is to induce isotype switch from IgG to IgE in individuals who already have a high affinity antibody response to this epitope [15–17].

In common with two previous studies on forest or national park workers the present study found a low prevalence of allergic symptoms related to eating red meat among the sensitised subjects [1]. This may reflect a common feature of most allergic diseases, which is that many subjects who are sensitised to a relevant antigen do not report symptoms. However, the cumulative data on forest workers suggests that the prevalence of symptoms is surprisingly low. This could suggest that tick bites in these workers who are often exposed to large numbers of tick bites, have a different immunological effect because of some aspect of their lifestyle. Currently, we do not understand why some subjects develop the full syndrome of AGS including allergic or anaphylactic reactions to mammalian meat or other tissues. However, preliminary data suggests this may take many years of repeated tick bites [18] while there may be other relevant factors in relation to diet, it seems unlikely that forestry workers in three countries are avoiding red meat.

Conclusion

This paper from London and Poland is about a detailed evaluation of forest workers, who had a high prevalence of tick bites, confirms the strong association between tick bites and IgE responses to alpha-gal. In addition, this is the best evidence yet from an infectious disease group that the presence of these IgE antibodies is not associated with evidence of infection with tick borne pathogens. Finally, they found a low incidence of allergic symptoms related to red meat among the sensitised subjects. The results suggest that these individuals could provide an interesting model to understand the reasons why so many of them do not have symptomatic responses to red meat.

Disclosure statement

No potential conflict of interest was reported by the author(s).