Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common autoimmune peripheral neuropathy but remains a rare disease with a prevalence of 0.8-8.9 cases per 100.000 [1, 2]. The disorder causes severe disability in more than 50% of the patients in a chronic-progressive course [1]. Diagnosis can be difficult given the heterogeneity of CIDP phenotypes. About 50% of the patients suffer from so-called atypical variants including Distal Acquired Demyelinating Polyneuropathy (DADS) in 25-35% of the cases, Multifocal Acquired Demyelinating Sensory And Motor Polyneuropathy (MADSAM) in 15% and rare variants such as pure sensory CIDP (10-13%), pure motor CIDP (<10%) and focal CIDP (2%) [3]. These CIDP subtypes are likely to differ with respect to underlying pathomechanisms and may necessitate different treatment approaches.

Despite recent progress, the underlying immunopathogenetic mechanisms remain poorly understood [4]. Both humoral as well as cellular immune responses are likely to play a role in the induction of autoimmune neuroinflammation, which leads to demyelination and axonal degeneration [4‐7].

Peripheral myelin antigens are promising auto-antigens in CIDP pathogenesis. Recently, we demonstrated higher frequencies of auto-reactive IFN-γ responses directed against the peripheral myelin antigens PMP-22 and P2 in treatment naïve patients who responded subsequently well to intravenous immunoglobulin (IVIG) treatment. Clinical improvement under IVIG-treatment correlated with the reduction of antigen-specific responses against PMP-22 and P2 [8].

Experimental studies in the EAN model of Guillain-Barré-Syndrom (GBS) support a pathogenic role of another compact myelin P0. Immunization with P0 180-199 is capable to induce EAN in wildtype-, IFN-γ knockout and TNF-α knockout mice [9‐11]. However, an evaluation in CIDP patients remains to be done.

Myelin basic protein (MBP) is a major constituent of the myelin sheath in the central and peripheral nervous system [12]. Whereas it has been established as an immunodominant auto-antigen for demyelination in the immunopathogenesis of Multiple Sclerosis (MS) its auto-reactive potential in CIDP remains elusive [13].

T cells can be differentiated into CD45RA+ CCR7+ naïve, CD45RA- CCR7- effector memory (TEM), CD45RA- CCR7+ central memory (TCM) and CD45RA+ CCR7-terminally differentiated effector memory (TEMRA) T cells [14]. Especially CD4+ T cells play a major role in CIDP immunopathogenesis [15‐17]. In blood and CSF of CIDP patients, significantly elevated frequencies of CD4+ TEM and CD4+ TCM were demonstrated, whereas long-term treated CIDP patients showed significantly reduced CD4+ memory subsets in contrast to untreated CIDP patients [17‐19].

Here, we hypothesize that autoreactive myelin-specific T cell responses as well as T cell memory subsets differ between atypical and typical manifestations of CIDP.

In the present study, typical CIDP differed from the group of atypical variants. Here, we found a stronger activated immune system in patients suffering from atypical variants of CIDP defined by a trend towards increased peripheral myelin antigen-specific (PMP-22, P0 180-199, MBP 82-100) T cell responses associated with a specific altered CD4+ memory compartment of increased CD4+ TEM and CD4+ TCM counts in the blood. Further we detected elevated T cell responses against antigens P0 180-199 and MBP 82-100 in CIDP patients which have not described before.

We confirmed or previous findings that changes of the T memory compartment is a common finding especially in untreated patients [8, 17], which is in contrast to Sanvito and colleagues who showed no differences in T cell subpopulation [23]. In the present study, we detected elevated TEM and TCM primarily in atypical CIDP patients. Clinical experience and studies suggest that typical CIDP patients respond better to therapy than atypical CIDP variants, especially DADS [24], which is in line with our presented data showing that 100% (9/9) of typical compared to 47% (8/17) of atypical CIDP patients were therapy-responders. The reason for different treatment responses of CIDP subtypes remains unknown. The higher specific immune responses against myelin-derived peptides in atypical compared to typical variants may be a cause for the lower treatment-responses. Likewise, the increased immune reactivity in atypical CIDP patients could result from insufficient treatment.

Recently, it has been demonstrated that CIDP patients show a diminished pro-regenerative function of Schwann cells leading to the axonal loss and therefore incomplete clinical recovery after treatment which is probably caused by inflammatory mediators [25]. Thus, differences in immune responses between typical and atypical CIDP we have demonstrated might also influence Schwann cell function resulting in different treatment responses and long-term outcome. The INCAT score was significantly lower in atypical cases. However, there was no difference in the time since diagnosis so that a longer disease course and hence pronounced disability and/or altered immune response is not the cause of this difference. Yet, we included mainly atypical case with mild motoric disability (6 patients with sensory CIDP [35.3%] and 5 patients with DADS [29.4%]) who are less often dependent on walking aids leading to lower INCAT disability scores.

Since we included mainly clinically unstable patients who had partly received treatment before, we are not able to answer this question at present. Based on previous results of reduced CD4+ memory subsets in GS-treated patients [17], it might be further argued that GS treatment may be efficient for this patient group. In contrast to Sanvito et al. [26], we identified higher IFN-γ responses to P2 and PMP22 peptides which have been more pronounced in the atypical compared to the typical CIDP subgroup. A higher number and proportion of atypical patients might explain this discrepancy as well as the fact that we included mainly clinically unstable and newly diagnosed patients.

Earlier publications detected P0 IgG-antibodies in CIDP patients and P0 180-199 specific T cell responses in spontaneous autoimmune polyneuropathy-mice [11]. Although EAN resembles Guillain-Barré-Syndrom (GBS) much more than CIDP, we regarded P0 as possible further candidate autoantigen of compact myelin for CIDP. Here, we detected elevated P0 180-199 specific T cell responses primarily in atypical CIDP.

Up to now, only little is known about the role of MBP 82-100 in the pathogenesis of CIDP even though MBP has been detected as part of the myelin sheath of peripheral nerves. Nevertheless, there is long-standing evidence that MBP 82-100 can induce neuroinflammation in autoimmune diseases [27]. Glatirameracetat, known antagonist of MBP 82-100 specific T cell receptor and part of MS therapy has been demonstrated to alleviate symptoms also in EAN- mice [28, 29]. Here, we demonstrated significantly elevated MBP 82-100 specific T cell responses in CIDP patients, again primarily in patients with atypical manifestations.

There is growing evidence for the autoimmune potential of antigens which are derived from non-compact myelin of the nodal/paranodal region such as neurofascin 155 of 186 leading to antibody response in distinct subgroups of CIDP or multifocal motoric neuropathy (MMN) [30‐33]. Thus, antigenic targets derived from both compact and non- compact myelin leading to humeral and/or cellular immune response may define underlying immune mechanism of different clinical phenotypes of CIDP.

Several limitations may have affected our results. First, our clinically heterogeneous group of atypical patients was too small to distinguish between subgroups of atypical CIDP, which would be necessary to characterize atypical subtypes and to define specific cut offs for our immunological parameters. Second, differences in gender and INCAT score between typical and atypical CIDP patients might have influenced our immunological findings. Third, we aimed to recruit treatment-naïve patients in active-unstable stages of the disease. However, only 46% of patients (12/26) were treatment-naïve at enrollment. Previous immunosuppressive and –modulating therapy might have influenced our immunological findings.

Higher myelin-antigen specific T cell responses together with elevated T cell memory subsets were found in atypical compared to typical CIDP patients suggesting different patterns of immune responses in clinically distinctive CIDP subgroups. Myelin as well as nodal/paranodal proteins might serve as candidate autoantigens to establish robust immune markers for CIDP subtype differentiation. Given the clinical diversity of CIDP a larger cohort study is warranted in order to establish those markers with reliable cut-off values.