METHODS:Retrospective case series including flow cytometric analyses and T-cell receptor (TCR) sequencing of peripheral blood mononuclear cells.
RESULTS:We describe 3 cases of alemtuzumab-treated patients with RRMS developing vitiligo 52, 18, and 14 months after alemtuzumab initiation. Histopathology shows loss of epidermal pigmentation with absence of melanocytes and interface dermatitis with CD8+ T-cell infiltration. Also compatible with pathophysiologic concepts of vitiligo, peripheral blood mononuclear cells of one patient showed high proportions of CD8+ T cells with an activated (human leukocyte antigen-DR+), memory (CD45RO+), and type 1 cytokine (interferon-γ + tumor necrosis factor-α) phenotype at vitiligo onset compared to a control cohort of alemtuzumab-treated patients with RRMS (n = 30). Of note, analysis of CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. We observed a predominance of single clones at baseline in this patient and alemtuzumab treatment did not substantially affect the proportions of most abundant clones over time.
CONCLUSION:The 3 cases represent a detailed description of vitiligo as a T-cell-mediated secondary autoimmune disease following alemtuzumab treatment. The prevailing concept of unleashed B-cell responses might therefore not cover all facets of alemtuzumab-related secondary autoimmunity. Mechanistic studies, especially on TCR repertoire, might help clarify the underlying mechanisms.
We know that some people do not deplete or deplete poorly and one of the people was relapsing on alemtuzumab and rituximab, so they were not doing a good job at controlling MS.
We are not told if there was CD8 depletion but as they were in skin lesions two months after alemtuzumab the answer has got to be that alemtuzumab was not effective.
Were antibodies related to Vitiligo antigens present? We do not know except that there were no CD20 B cells in lesions when looked for.
It is funny that CD8 is highlighted as a problem in vitiligo, but it is not considered as the main problem in MS, yet we see that CD8 infiltrates are the dominant lymphocyte subsets in MS. Therefore is it simply the mechanism that allows MS to return occurring in people with a propensity to have MS and Vitiligo?.
“Vitiligo is a long-term skin condition characterized by patches of the skin losing their pigment. The patches of skin affected become white and usually have sharp margins. The hair from the skin may also become white.The exact cause of vitiligo is unknown. It is believed to be due to genetic susceptibility, that is triggered by an environmental factor such that an autoimmune disease occurs. This results in the destruction of skin pigment cells.
The TYR gene encodes the protein tyrosinase, which is not a component of the immune system, but is an enzyme of the melanocyte that catalyzes melanin biosynthesis, and a major autoantigen in generalized vitiligo
Studies revealing that melanocyte-specific antibodies and cytotoxic T cells have been detected in the peripheral blood of vitiligo patients supports the autoimmune hypothesis. The cytotoxicity of CD8+ T cells to melanocytes is considered to make a key contribution to the pathogenesis of non-segmental vitiligo. The autoimmune response is suggested to trigger the vitiligo but is not the main factor that affects the extent and duration of the disease”
There is no mention of whether these people had melanocyte-related antibody.
In this study they look at the CD8 TCR repertoire in this patient revealed a highly increased clonality and reduced repertoire diversity compared to healthy controls and treatment-naive patients with RRMS. This suggests that they have found a clone expanded by disease. They should now be able to find the antigen to which they react. It could be a vitiligo cause or it could be anti-viral response. They observed single clones and limited diversity.
Xu H, Bendersky VA, Brennan TV, Espinosa JR, Kirk AD. IL-7 receptor heterogeneity as a mechanism for repertoire change during postdepletional homeostatic proliferation and its relation to costimulation blockade-resistant rejection. Am J Transplant. 2018 Mar;18(3):720-730.
Zwang NA, Turka LA. Homeostatic expansion as a barrier to lymphocyte depletion strategies. Curr Opin Organ Transplant. 2014 Aug;19(4):357-62.
Jones JL, Thompson SA, Loh P, Davies JL, Tuohy OC, Curry AJ, Azzopardi L, Hill-Cawthorne G, Fahey MT, Compston A, Coles AJ. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20200-5
In the paper it was mentioned that Interleukin-21 may drive this. However in other papers it is IL-7 (IL-7R is one of the first Non-major histocompatibility complex genes associated with MS Susceptibility) and IL-15.
However, as cells expand to fill the space, clones will get expanded.
So did it make things worse? Apparently not, but the trial was stopped years early suggesting something was wrong.
Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA.T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014 Mar;124:1168-72. We found that HSCT has distinctive effects on CD4+ and CD8+ T cell repertoires. In CD4+ T cells, dominant TCR clones present before treatment were undetectable following reconstitution, and patients largely developed a new repertoire. In contrast, dominant CD8+ clones were not effectively removed, and the reconstituted CD8+ T cell repertoire was created by clonal expansion of cells present before treatment. Importantly, patients who failed to respond to treatment had less diversity in their T cell repertoire early during the reconstitution process