Marinos C. Dalakas

Complement comprises a group of plasma and membrane proteins that provide an effective bridging function for innate and adaptive humoral immunity. Understanding complement pathophysiology is fundamental given that inappropriate complement function in host defence can lead to infectious diseases and inefficient disposal of altered, damaged or senescent cells can lead to or enhance autoimmune neurological processes. Although the rising number of approved drugs targeting complement pathways remains primarily focused on diseases with complement-fixing pathogenic antibodies (such as myasthenia gravis and neuromyelitis optica spectrum disorder), a robust pipeline of emerging treatments holds promise for expanding complement-targeted therapies to a broader spectrum of autoimmune neurological diseases, such as multiple sclerosis and even neurodegenerative diseases such as Alzheimer disease or amyotrophic lateral sclerosis. This Review presents insights into complement biology as it relates to the development or initiation of autoimmune and possibly degenerative diseases affecting the central and peripheral nervous systems or muscle. The effects, merits, risks and challenges of marketed drugs or biologic agents in ongoing phase I–III clinical trials engineered to inhibit proximal or distal components of the complement cascade are also discussed. Anti-complement therapeutics are destined to change the treatment of autoimmune neurologic conditions in which the therapeutic landscape is now becoming crowded with biologic agents targeting other key autoimmunity factors.

T cells, genetically modified to express chimeric antigen receptors (CAR T), successfully used in hemato-oncologic malignancies, are showing promising and sustained benefits in refractory autoimmune neurological diseases, including Myasthenia Gravis, stiff-person syndrome, neuromyelitis optica, myositis, autoimmune neuropathies, and multiple sclerosis. Several reported patients with a steadily progressive disease and evolving disability unresponsive to available therapies, including rituximab and new biologics, after 2–3 months of treatment with CARs targeting CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts exhibit impressive, long-lasting, and drug-free clinical improvements with the potential for immune reset shifting immunity to a healthy state without the need for continuing more immunotherapy cycles. The review discusses what the unmet needs are with the present neuroimmunotherapeutics pointing out the disease stage and patient subsets for which CAR T-therapy is most suitable highlighting that CAR T should be applied in the early stages of disability development when patients reach early-active/refractory status rather than waiting for very late disease progression when neurological deficits might be irreversible. The future trajectory of CAR T cells is also described as a promising means destined to change the present therapeutic algorithm in all neuro-autoimmunites, even offering a promising path toward a cure, pointing out that, in contrast to currently approved biologics that selectively target one immunoregulatory factor, CD19 CAR T cells exert effects even beyond B cells, cross the blood–brain barrier and lymphoid tissues, and expand as “living cells” to memory cells ensuring sustained long-term benefits. Key therapeutic uncertainties and practicalities are however highlighted, including the exact duration of CAR T-cell therapy-induced drug-free remissions, logistical challenges, economic limitations, and the need for extensive collaborative efforts with experts in specialized clinical centers.

Chimeric antigen receptor (CAR) T cells are genetically modified T cells expressing CARs, initially developed to recognize tumor antigens and kill cancer cells that evade T-cell recognition. Because of their impressive success in hemato-oncologic malignancies, CAR T cells are being repurposed with redesigned constructs for safety and sustained efficacy to target refractory systemic autoimmune or neurologic diseases. The CD19 CAR T cells-targeting those CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts-are now extensively explored in refractory neuroautoimmunities with promising benefits based on case series in patients with myasthenia gravis (MG), stiff person syndrome (SPS), neuromyelitis, myositis, and multiple sclerosis; some patients with MG and SPS with steadily progressive and disabling disease refractory to all available therapies, including rituximab and new biologics, exhibit impressive clinical improvements with long-lasting benefits. The review, triggered by these early results and ongoing trials, addresses what these cells are and why they show effectiveness not only in antibody-mediated B-cell neurologic diseases unresponsive to available anti-B-cell agents but also in patients with nonpathogenic antibodies, implying effects even beyond B cells; points out that CARs are "living cells" penetrating physiologic barriers, such as the blood-brain barrier, expanding within tissues to memory cells ensuring sustained effects; describes the process and challenges of preparing and administering CAR T cells and their safety profile stressing the differences in toxicities when treating autoimmunites vs malignancies; and highlights that CD19 CAR T cells can successfully target even 2 different autoimmune diseases in the same patient, such as SPS and MG, offering promising prospects of changing the therapeutic algorithm in all neuroautoimmunities with potential for achieving even an immune reset shifting immunity to a healthy state.

The aim of this study was to identify genetic markers and immunologic characteristics of glutamic acid decarboxylase (GAD) antibody-positive patients with stiff-person syndrome (SPS). We conducted systemic immunogenetic studies in 11 GAD-positive patients: 8 with sporadic SPS and 3 from a three-generation family with very high GAD-ab titers but diverse symptomatology (one with GAD-epilepsy and SPS and 2 only with diabetes), by performing complete immunologic profile and whole-exome sequencing analysis. Two genes expressed in immune and neuronal tissues were identified: the ORAI1 that codes for a calcium release-activated channel protein with a role in the activation of T lymphocytes and the LILRA4 that encodes an IgG-like cell surface protein expressed in plasmacytoid dendritic cells. An important finding was the identification of 7 genetic polymorphisms in the novel Kallikrein 10 (KLK10) gene, shared by all 9 typical patients with SPS, as verified by Sanger sequencing, but not in the 2 GAD-positive family members with diabetes or the GAD-negative controls. To further verify these findings, Sanger sequencing was performed in 10 more patients with SPS and 15 autoimmune controls collectively confirmed that among a total of 39 tested samples, 95% of the 19 patients with SPS were homozygous or heterozygous for all 7 KLK10 variants while 90% of the 20 controls had the wild type or were heterozygous. KLK10 is a peptidase expressed in the choroid plexus epithelium and neuroendocrine organs and participates in the initiation of systemic inflammatory responses and immune-modulated disorders through proteolytic cascades. KLK10 is a novel and potentially key genetic marker in patients with SPS that can contribute to disease pathogenesis by altering protease activity or the expression of neuron-to-immune cell signaling facilitating GAD autoimmunity. Along with the 2 newly identified immune-related genes, KLK10 is likely an interplay between genetic predisposition and immune dysregulation, necessitating the need to explore their significance as susceptibility disease factors and possibly as novel therapeutic targets.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most frequently observed autoimmune neuropathy in patients with diabetes mellitus (DM). While intravenous immune globulin (IVIG) is a well-established treatment for CIDP, its efficacy in diabetic patients remains uncertain due to their exclusion from prior randomized trials, largely because of concerns about confounding diabetic axonal neuropathy. Objectives: To evaluate the effectiveness of IVIG therapy in CIDP patients with diabetes mellitus (CIDP-DM) compared to those without diabetes (CIDP). Design: Multi-center, prospective, observational study after at least 3 monthly infusions of IVIG therapy. Methods: Thirty-six patients meeting diagnostic criteria for CIDP were enrolled and stratified into CIDP or CIDP-DM. All patients were followed for a minimum of 3 months after initiating IVIG therapy. Clinical outcomes were assessed at baseline (visit #1) and after 3 monthly IVIG infusions (visit #4) using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Score, the Rasch-built Overall Disability Scale, and the Chronic Acquired Polyneuropathy Patient-reported Index, measured at baseline and at the point of maximal improvement. Results: No significant differences were observed in clinical outcomes, treatment-related adverse events, or tolerance between CIDP and CIDP-DM groups, indicating comparable effectiveness of IVIG therapy. However, subgroup analyses revealed that longer duration of diabetes and elevated HbA1c levels were associated with delayed response to IVIG, likely due to cumulative axonal degeneration. Conclusion: Despite the small number of enrolled patients, IVIG appears equally effective in CIDP patients with and without diabetes. Earlier initiation of IVIG treatment should be considered in CIDP-DM patients to mitigate potential delays in therapeutic response associated with a possibly chronic diabetic neuropathy-related component.

In the past decade, significant progress has been made on the understanding of IgG4-mediated autoimmune diseases, of both the central and the peripheral CNS. In addition to the description of diverse antigenic targets, the description of IgG subclasses associated with specific pathogenic autoantibodies has provided useful insights into the pathophysiology and, more importantly, into the therapeutic implications of the autoantibody subclasses. This understanding has affected how myasthenia gravis, autoimmune encephalitis, and autoimmune neuropathies are treated. In the case of autoimmune neuropathies, the discovery of antigenic targets located at the node of Ranvier has led to the definition of a new diagnostic category, the autoimmune nodopathies, which differentiate them from the classical forms of Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy. These neuropathies including those caused by autoantibodies targeting contactin-1, contactin-associated protein 1, and neurofascin are mainly, though not always exclusively, mediated by IgG4 antibodies, and respond to therapies similarly to other IgG4-mediated neurologic and non-neurologic diseases, providing evidence that not only the antigenic target but also the autoantibody subclass play a role in understanding both the disease pathophysiology and response to therapies. In this article, we describe the history and main findings on autoimmune nodopathies; highlight the particularities and similarities of IgG4-mediated neurologic diseases, including autoimmune nodopathies and neuromuscular junction and certain CNS disorders; elaborate on the unique functional properties of IgG4 in influencing their specific response to immunotherapies stressing the rationale of the most suitable present and future targeted therapies; and discuss how best to apply and monitor maintenance therapies for inducing disease stability in all IgG4 neurologic autoimmunities including the need for potential future biomarkers.