Study of Pathogenic Mechanisms and Identification of Novel Autoantibodies in Autoimmune Encephalitis

NCT07477015 | Recruiting

• 1 other identifier: 6379
• Study Type: observational
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

Autoimmune encephalitis is a debilitating neurological disorder that usually appears as a rapidly progressive form of brain dysfunction, typically developing in less than six weeks, caused by inflammation in the brain. These conditions show a wide range of clinical and immunological presentations and are generally divided into two main types. The first type includes what are called paraneoplastic syndromes. In these cases, the immune system produces antibodies in response to a tumor that mistakenly target parts of the nervous system. The antibodies are not directly harmful themselves, but they are a sign that the immune system has launched a T-cell-driven attack on brain tissue because it recognizes a protein that's found both in the tumor and in the nervous system. These forms usually follow a single, non-repeating course and tend to respond poorly to treatment, which mostly focuses on removing or treating the underlying tumor and using immunotherapy to reduce the immune response. The second type includes what we more properly call autoimmune encephalitis, where the immune system produces antibodies that directly attack proteins on the surface of neurons or on synaptic receptors in the brain. Unlike in paraneoplastic syndromes, these antibodies are directly responsible for the disease, and they don't usually indicate the presence of a tumor. Most people with this type of autoimmune encephalitis-around 70% to 80%-respond well to treatment with immunotherapy and can make a good or even full recovery. However, in about 20% of cases, the disease can come back or lead to long hospital stays, with a slower or only partial recovery. There is also a third group of autoimmune encephalitides where the antibodies target synaptic proteins. These may or may not be linked to cancer, and the proteins they target are usually found inside the cells rather than on their surface. A fourth group includes what are called seronegative autoimmune encephalitides. These are cases that meet the clinical criteria for autoimmune encephalitis, but no specific antibodies have been identified so far. Among the autoimmune neurological disorders without known antibodies is Susac syndrome, a rare condition that affects the brain, the retina, and the inner ear. It's especially interesting because its features suggest the involvement of antibodies, even though no disease-causing antibodies have yet been found. The diagnosis of autoimmune encephalitis is based on clinical signs and symptoms, the detection of specific antibodies in blood or spinal fluid, and, in paraneoplastic cases, identifying the underlying tumor. To detect autoantibodies, doctors use various lab techniques, including immunoblotting and different types of immunofluorescence tests-some based on cultured cells, others on brain tissue from rodents. Despite important progress in recent years, many cases of autoimmune encephalitis remain undiagnosed. One reason is that the disease can begin with vague or incomplete symptoms, making it difficult to recognize. Another issue is that current testing methods might not be sensitive enough to detect all possible antibodies. This means that the group of patients diagnosed with seronegative autoimmune encephalitis might actually include people who have antibodies we just haven't discovered yet. In many cases, especially in the seronegative forms, the exact cause of the disease is still not fully understood. The main goal of this study is to better understand how autoimmune encephalitis develops, especially in cases involving antibodies that target proteins on the surface of brain cells-such as NMDAR, GABABR, AMPAR, LGI1, and DNER-as well as in seronegative autoimmune encephalitis and in Susac syndrome. A second goal is to try to discover new autoantibodies that could explain the disease in patients who currently test negative.

Conditions

Autoimmune Encephalitis

Outcome Measures

Primary Outcomes (1)

• Generate human recombinant monoclonal antibodies (mAbs) specific to the target antigen from patients' B cells

  To generate monoclonal antibodies (mAbs) from autoreactive B cells of patients, we will use LIBRA-seq (Linking B-cell Receptor to Antigen specificity through sequencing), a recently developed technique.

  12 months

Secondary Outcomes (1)

• Isolate polyclonal IgG from the serum of patients with autoimmune encephalitis associated with known antibodies, seronegative autoimmune encephalitis, and Susac syndrome

  3 months

Other Outcomes (3)

• Identify the autoantibody target antigen in samples from patients with seronegative autoimmune encephalitis and Susac syndrome using immunoprecipitation with electrophoresis and mass spectrometry

  12 months

• Investigate and confirm the tissue reactivity of serum and cerebrospinal fluid samples, polyclonal IgGs, and mAbs on neuronal cultures and rat brain sections using immunohistochemistry techniques

  6 months

• Identify the autoantibody target antigen in samples from patients with seronegative autoimmune encephalitis and Susac syndrome using antigen protein microarrays

  12 months

Study Arms (2)

autoimmune encephalitis group

Patients diagnosed with encephalitis associated with antibodies against NMDAR, GABABR, AMPAR, LGI-1, DNER, seronegative autoimmune encephalitis, and Susac syndrome.

Control Group

A control group consisting of patients with other neurological disorders, in whom the presence of antibodies against neuronal antigens has been excluded, will also be enrolled.

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

For the autoimmune encephalitis group: Patients diagnosed with encephalitis associated with antibodies against NMDAR, GABABR, AMPAR, LGI-1, DNER, seronegative autoimmune encephalitis, and Susac syndrome belonging to the IRCCS Fondazione Policlinico A. Gemelli on an outpatient basis, who meet the inclusion and exclusion criteria of the study, will be enrolled consecutively. For the control group: patients with other neurological disorders, in whom the presence of antibodies against neuronal antigens has been excluded, belonging to the IRCCS Fondazione Policlinico A. Gemelli on an outpatient basis, who meet the inclusion and exclusion criteria of the study, will be enrolled consecutively.

You may qualify if:

• Patients \> 18 years of age
• Patients able to provide informed consent
• For the patient group: patients diagnosed with autoimmune encephalitis associated with anti-NMDAR, GABABR, AMPAR, LGI-1, DNER antibodies, seronegative autoimmune encephalitis, or Susac syndrome, without other concomitant autoimmune diseases
• For the control group: patients without a diagnosis of autoimmune encephalitis associated with anti-NMDAR, GABABR, AMPAR, LGI-1, DNER antibodies, seronegative autoimmune encephalitis, or Susac syndrome
• For the control group: patients with other neurological disorders in whom the presence of antibodies against neuronal antigens has been excluded

You may not qualify if:

• Patients ≤ 18 years of age
• Deceased patients

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

Fondazione Policlinico Universitario A. Gemelli IRCCS

Rome, RM, 00168, Italy

RECRUITING

MeSH Terms

Conditions

Autoimmune Diseases of the Nervous System

Condition Hierarchy (Ancestors)

Nervous System Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Raffaele Iorio

  Fondazione Policlinico Universitario A. Gemelli, IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Raffaele Iorio

CONTACT

+390630155930; raffaele.iorio@policlinicogemelli.it

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: OTHER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 14, 2025
• First Posted: March 17, 2026
• Study Start: July 31, 2025
• Primary Completion (Estimated): July 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: March 17, 2026

Record last verified: 2025-07

Locations

IT (1)