CD80+ and CD86+B cells as biomarkers and possible therapeutic targets in HTLV-1 associated myelopathy/tropical spastic paraparesis and multiple sclerosis

Abstract

BackgroundHuman T-cell lymphotropic virus (HTLV-1) is the causative agent of the incapacitating, neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Currently, there are no disease-modifying therapies with long-term clinical benefits or validated biomarkers for clinical follow-up in HAM/TSP. Although CD80 and CD86 costimulatory molecules play prominent roles in immune regulation and reflect disease status in multiple sclerosis (MS), data in HAM/TSP are lacking.MethodsUsing flow cytometry, we quantified ex vivo and in vitro expression of CD80 and CD86 in PBMCs of healthy controls, HTLV-1-infected individuals with and without HAM/TSP, and MS patients. We hypothesized ex vivo CD80 and CD86 expressions and their in vitro regulation by interferon (IFN)-α/β mirror similarities between HAM/TSP and MS and hence might reveal clinically useful biomarkers in HAM/TSP.ResultsEx vivo expression of CD80 and CD86 in T and B cells increased in all HTLV-1 infected individuals, but with a selective defect for B cell CD86 upregulation in HAM/TSP. Despite decreased total B cells with increasing disease duration (p = 0.0003, r = −0.72), CD80+ B cells positively correlated with disease severity (p = 0.0017, r = 0.69) in HAM/TSP. B cell CD80 expression was higher in women with HAM/TSP, underscoring that immune markers can reflect the female predominance observed in most autoimmune diseases. In contrast to MS patients, CD80+ (p = 0.0001) and CD86+ (p = 0.0054) lymphocytes expanded upon in vitro culture in HAM/TSP patients. The expansion of CD80+ and CD86+ T cells but not B cells was associated with increased proliferation in HTLV-1 infection. In vitro treatment with IFN-β but not IFN-α resulted in a pronounced increase of B cell CD86 expression in healthy controls, as well as in patients with neuroinflammatory disease (HAM/TSP and MS), similar to in vivo treatment in MS.ConclusionsWe propose two novel biomarkers, ex vivo CD80+ B cells positively correlating to disease severity and CD86+ B cells preferentially induced by IFN-β, which restores defective upregulation in HAM/TSP. This study suggests a role for B cells in HAM/TSP pathogenesis and opens avenues to B cell targeting (with proven clinical benefit in MS) in HAM/TSP but also CD80-directed immunotherapy, unprecedented in both HAM/TSP and MS.

Evaluation of HTLV‐1 HBZ and proviral load, together with host IFN λ3, in pathogenesis of HAM/TSP

“…The host's immune response against HTLV‐1‐infected T‐cells is induced by CTLs in the central nervous system, resulting in the production of Th1 cytokines such as IFN γ, IL‐2, and TNF‐α by activated cells, which leads to the destruction of neurons [Espíndola et al, ]. Expression of pro‐inflammatory IFN γ is intensified in HAM/TSP patients and ACs compared to healthy people [Menezes et al, ]. In addition to these cytokines, in the present study the expression of IFN λ3 was evaluated in both sets of patients.…”

“…The viral burden is presented as a section of PBMCs that comprise integrated proviruses (the so‐called PVL) [Niederer et al, ]. While the heterogeneity of the disease outcome is still unclear, it is probably specified by the interaction between viral and host immune factors such as Tax, HBZ, PVL, and the host's genetic and epigenetic characteristics and cytokines [Menezes et al, ]. Andrade et al [] found a drastic correlation between Tax and HBZ mRNA expression in HAM/TSP individuals and their linkage with various markers of the neurological disease.…”

“…In spite of HIV‐positive patients, most (>90%) HTLV‐1‐positive individuals remain healthy, as do asymptomatic carriers (ACs) [Hanon et al, ]. A small proportion of HTLV‐1‐infected individuals develop a type of neoplastic disease called adult T‐cell leukemia/lymphoma (ATLL) and the inflammatory condition of HTLV‐1‐associated myelopathy/tropical spastic paraparesis (HAM/TSP) [Menezes et al, ]. HAM/TSP is a chronic inflammatory disease that slowly develops into a neurological disorder of the dynamic‐sensory system, and causes progressive muscle weakness that results in hyper‐reflexia of the lower limbs, sensory disturbance, urinary incontinence, and impotence [Verdonck et al, ].…”

An evolutionary recent IFN-IL-6-CEBP axis is linked to monocyte expansion and tuberculosis severity in humans

“…Furthermore, our results show that live Mtb is a potent stimulus to induce ISGs HSPCs require further investigation. Of note, in our previously characterized cohort of multiple sclerosis patients (Menezes et al, 2014;Van Weyenbergh, Wietzerbin, Rouillard, Barral-Netto, & Liblau, 2001), IFN-β therapy in vivo did not significantly change monocyte or lymphocyte counts, nor did it increase the ML ratio after three months of treatment in patients with documented clinical response (data not shown), supporting the idea that type I IFN by itself is not sufficient to cause monocyte expansion in vivo.…”

A combination of the activation marker CD86 and the immune checkpoint marker B and T lymphocyte attenuator (BTLA) indicates a putative permissive activation state of B cell subtypes in healthy blood donors independent of age and sex

“…If our finding is true and there actually is a repeatable difference between men and women in CD86 expression on some B cell subtypes, our data indicate that these differences are found in more mature cell sybtypes, PB versus pre-PB, and SM and NSM versus DNM. One previous study describes a clear sex dependent difference in CD80 expression on B cells in neuroinflammatory diseases, independent on disease severity [26]. There is a CD86 polymorphism resulting in higher CD86 expression on B cells [27], and it cannot be excluded that there was an increased frequency of men with that allele in our cohort.…”