Research: skin reactions to glatiramer acetate

Mayorga et al. Immunological mechanisms underlying delayed-type hypersensitivity reactions to glatiramer acetate. Ann Allergy Asthma Immunol. 2012;109(1):47-51.

BACKGROUNDDelayed-type hypersensitivity (skin allergy reaction) to glatiramer acetate is rare, and the underlying immunological mechanisms are not completely understood.

OBJECTIVE: To study the immunologic response in 2 patients with multiple sclerosis who developed maculopapular exanthema (skin rash, with bumps) related with the administration of glatiramer acetate.

METHODS: The allergologic study included general blood tests, viral serologic tests, and skin tests (patch and intradermal tests). The immunologic study was performed in skin biopsy specimens by immunohistochemistry and in the peripheral blood by flow cytometry and the lymphocyte transformation test.

RESULTS: Skin test results were negative in both patients, and the diagnosis was confirmed by a drug provocation test. The evaluation of the acute phase showed an increase in the percentage of CD8 T lymphocytes (>50%) and the percentage of cells expressing skin-homing receptor (cutaneous lymphocyte-associated antigen) (>70%) and chemokine receptors (CCR4 and CXCR3) at T1. A positive proliferative response was observed in T lymphocytes (stimulation index [SI] = 3.5 in patient 1 and 3.59 in patient 2), especially the CD8(+) subpopulation (SI = 5.5 and 4.6 in patients 1 and 2, respectively), and NK lymphocytes (SI = 3.9 and 8.5 in patients 1 and 2, respectively) after glatiramer acetate stimulation.

CONCLUSION: This study demonstrates the important role of T(H)1 cells expressing skin-homing receptors in delayed-type hypersensitivity reactions to glatiramer acetate. A lymphocyte transformation test revealed a specific glatiramer acetate recognition by T lymphocytes and NK lymphocytes.

Skin tests for allergies are usually immediate reactions within minutes and causes itching and swelling and reddening, which is a type I allergic reaction a type IV reaction is delayed taking 24-48 hours to manifest itself. This causes swelling and reddening.

Glaterimer acetate is a random copolymer of 4 amino acids. The original idea was that the four amino acids were selected as they were present in myelin basic protein (MBP) and it was thought that autoimmunity to myelin basic protein was the problem in MS. Glaterimer acetate somehow mimicked MBP and switched off the immune response.

The problem with this, is the logic. In my mind even if MS is an autoimmune disease, MBP is not a very good candidate to be an autoimmune target. Why? It is found in both CNS and peripheral nerve and MS is essentially a disease of the CNS. When you look not many cells react with MBP. If they do you can get a poly neuropathy (that affect peripheral nerves). I think the reason why it was studied so much in the 1970s was because it was the only myelin sheath protein that could be purified and made as it was water soluble and so could be used in cell culture. The CNS -specific proteins were either only fat soluble and so could not easily be purified or was present in only very minor amounts and so difficult to study until the 1980s and 1990s when these molecules could be syntheitically made.

What this study shows that some times glaterimer acetate can cause an allergic reaction. This is manifest by skin reactions in the injection site. It this concoction was so similar to MBP, as was claimed originally, you would expect these individuals to get some form of encephalitis (Brain swelling). They didn't so this not likely to be how it work. 

However since the 1970s when glaterimer acetate was first made, it has been reported to work via so many mechanisms. These follow the flavour of the month/year with regard to mechanism of control og the immune response, that we will probably not know how it works. My guess is it just swamps the antigen presenting cells with peptide that can not function properly.

CoI: None