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Background and Aims

The aim of this narrative review is to provide an overview of the literature on the possible immunologic pathophysiology of psychiatric manifestations of neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods

A systematic search on PubMed was conducted. English studies with full text availability that investigated the correlation between blood-brain barrier (BBB) dysfunction, intrathecal synthesis of antibodies, antibodies, cytokines, chemokines, metalloproteinases, complement and psychiatric NPSLE manifestations in adults were included.

Results

Both transient BBB-dysfunction with consequent access of antibodies to the cerebrospinal fluid (CSF) and intrathecal synthesis of antibodies could occur in psychiatric NPSLE. Anti-phospholipid antibodies, anti-NMDA antibodies and anti-ribosomal protein p antibodies seem to mediate concentration dependent neuronal dysfunction. Interferon-α may induce microglial engulfment of neurons, direct neuronal damage and production of cytokines and chemokines in psychiatric NPSLE. Several cytokines, chemokines and matrix metalloproteinase-9 may contribute to the pathophysiology of psychiatric NPSLE by attracting and activating Th1-cells and B-cells.

Conclusions

This potential pathophysiology may help understand NPSLE and may have implications for the diagnostic management and therapy of psychiatric NPSLE. However, the presented pathophysiological model is based on correlations between potential immunologic etiologies and psychiatric NPSLE that remain questionable. More research on this topic is necessary to further elucidate the pathophysiology of NPSLE.

Background and Aims

The aim was to identify association of psychiatric manifestations and laboratory data in AIT patients.

Methods

We studied 100 patients with AIT. 25% of our patients had an AIT in combination with different psychiatric disorders. We noticed different psychiatric manifestations in both groups. Patients with AIT had phobias (52%) and sleep disorders (52%). Patients with AIT in combination of psychiatric disorder had phobias (44%), generalized anxiety (92%), sleep disturbances (64%), irritability (40%), panic attacks (52%), hallucinations (72%), delirium (80%), depression (32%), attention deficit (44%). We studied such parameters as antiTPO, antiTG, TSH, FT3, FT4, prolactin and ANA.

Results

We found significant correlations between low level of FT4 and attention deficit (β=-1.9; p=0.003), irritability (β=-2,7;p<0,001), generalized anxiety (β=-1,7;p=0,005), delirium (β=-3,0,p<0,001), hallucinations (β=-1,9;p=0,003), sleep disturbances (β=-1,6;p=0,029). A significant correlation was found between high level of TSH and attention deficit (β=2,5;p=0,009), panic attacks (β=2,5;p=0,009), irritability (β=3,7;p=0,001), delirium (β=3,0;p=0,003). Between high level of antiTPO and attention deficit (β=0,7;p=0,003), panic attacks (β=0,5;p=0,01), irritability (β=0,5;p=0,017), generalized anxiety (β=0,7;p<0,001), depression (β=0,5;p=0,015), delirium (β=0,8;p<0,001) a significant correlation was also detected. There was a significant correlation between high level of prolactin and sleep disturbances (β=1,1;p=0,028), generalized anxiety (β=3,1;p<0,001), depression (β=1,5;p=0,049), delirium (β=2,7;p<0,001). Thus we have detected that correlations between sleep disturbances, phobias and the levels of FT4 and prolactin are significant regardless of the presence of psychiatric disorder.

Conclusions

Several immuno-endocrine parameters significantly correlated to psychic symptoms . The same time correlations between sleep disturbances, phobias and the levels of FT4 and prolactin didn’t depend on the presence of psychiatric disorder.

Background and Aims

Sera autoantibodies against Fibroblast Growth Factor Receptor 3 (FGFR3) were recently identified in a subgroup of 15% of patients with sensory neuropathy (SN). In order to better understand the anti-FGFR3 autoantibodies’ role, we aimed for confirming their intracellular target and to detecting their epitope(s) more precisely.

Methods

In the mapping approach, 25 amino acids (aa) long peptides covering the FGFR3 full-length or intracellular sequence, were spotted onto a cellulose membrane. A second version was phosphorylated at their natural sites. In the screening approach, 7 cytosolic candidate epitopes were screened with 68 anti-FGFR3-positive SN patients and 35 HC. Clinical and paraclinical data were compared between the different subgroups of patients.

Results

Mapping with 4 anti-FGFR3-positive sera resulted in major epitope candidates in the intracellular domain. Furthermore, the reactivity of several epitope regions strongly depended on their phosphorylation state. In the systematic screening approach, 15 of 66 anti-FGFR3-positive SN patients significantly bound 5 epitopes: 4 cases bound to 3 epitopes in the juxtamembrane domain; 11 cases bound to 2 epitopes in the tyrosine kinase domain (TKD). The identified epitopes cover 6/15 functionally relevant sites. The epitope with most frequent reactivity was located in the activation loop. Moreover, patients with anti-FGFR3 antibodies recognizing TKD exhibited a higher anti-FGFR3 antibody level and a more severe clinical and electrophysiological impairment than others.

Conclusions

Anti-FGFR3 autoantibodies target ≥ 5 different functionally relevant epitopes on the FGFR3 protein, suggesting pathogenetic roles of the autoantibodies. To our knowledge, our results represent the first description of phosphorylation state-dependent autoantibodies in a neurological disease.

Background and Aims

The autoimmune hypothesis of schizophrenia has become the most relevant in the last decade. There is a theory that schizophrenia is an autoimmune disease caused by the autoantibodies that affect neural receptors of the limbic system (anti-neuronal antibodies, autoantibodies against the brain vascular endothelium, abzymes with RNase and protease activities).

Methods

We analyzed a possible role of autoimmune processes in the pathogenesis of schizophrenia and the dynamics of views on this issue.

Results

An increase in the levels of proinflammatory cytokines and chemokines, as well as a decrease in the levels of anti-inflammatory ones, contribute to schizophrenia risks. Schizophrenia often occurs in patients and their first-degree relatives with various autoimmune diseases.

Risks of an autoimmune process and development of schizophrenia are associated with: an impaired functioning of dopaminergic and glutamatergic systems in the brain, kynurenine pathway (overproduction of quinolinic, anthranilic and kynurenic acids), stress, and increased intestinal permeability, microflora alterations as well as food antigens’ effects. Various infections at different stages of ontogenesis (Coxsackie, Hepatitis C viruses, Herpesviridae, influenza, SARS, Toxoplasma, Borrelia, etc.) also can play the triggering role in pathologic autoimmunity and schizophrenia.

Cases of schizophrenia associated with autoimmune mechanisms (including autoimmune encephalitis with its autoantibodies against various neuronal antigens) are characterized by severe cognitive and psychotic symptoms and less favorable prognosis.

Conclusions

Thus, autoimmune alterations in combination with other mechanisms may be important factors in the etiology and links in the pathogenesis of schizophrenia.

Acknowledgments: This work was supported by the grant of the Russian Federation Government, contract 14.W03.31.0009

Background and Aims

Although nervous system involvement may occur in Eosinophilic Granulomatosis with Polyangiitis (EGPA), its clinical manifestations and pathophysiology are still poorly understood. Our goals are: 1-characterize CNS/PNS involvement; 2-analyze if there is a difference in biological markers in patients with and without neurological manifestations.

Methods

Retrospective observational study, including EGPA patients with and without neurological manifestations. Demographics, clinical data and biological markers were collected. Descriptive and inferential statistics were applied.

Results

A total of 16 cases were analyzed, 9 with (group-1) and 7 without (group-2) neurological involvement. Patients from group-1 were older at EGPA diagnosis. Neurological involvement preceded EGPA diagnosis in 5 patients, and occurred during follow-up in 4 patients after a median of 4,5 years. Main CNS manifestations were stroke (n=2), bilateral central retinal artery occlusion (n=1), labyrinthine haemorrhage (n=1) and compressive dorsal myelopathy due to extradural granulation tissue (n=1). Main PNS manifestation were axonal polyneuropathy (n=3), sensorineural hearing loss (n=3) and multiplex mononeuropathy (n=1). Two patients had both PNS and CNS affected. There were no statistical differences concerning biological markers (eosinophil count, MPO titers) between the 2 groups. All patients were treated with immunosuppressive drugs, with 2 patients unresponsive to treatment belonging to group-1.

Conclusions

EGPA related nervous system manifestations can be very pleomorphic, highlighting 4 distinct neurological scenarios in our sample - peripheral neuropathy, VIII cranial nerve neuropathy, ischemic and hemorrhagic lesions and compressive myelopathy. In our cohort, patients with neurological manifestations did not have different eosinophilic count and MPO titer comparing with patients without neurological involvement.

Background and Aims

Proteins in their native state have the hydrophobic amino acid sequences buried (e.g., within the core of their globular structure). Protein misfolding exposes hidden hydrophobic residues and makes proteins immunogenic. Misfolded proteins such as Abeta, Alpha-synuclein, etc. acumulate in neurodegenerative diseases. Antibodies, including the anti-tau antibodies, anti α-synuclein, anti-Aβ, etc., were repeatedly found in neurodegenerative diseases. In Alzheimer´s disease, new study has revealed that the number of plasma B cells producing anti-Aβ42 antibodies is significantly higher in AD patients when compared to healthy controls. Are neurodegenerative diseases autoimmune conditions in origin?

Methods

original article & review

Results

The structural homology in molecular mimicry has traditionally been related to the primary structure of proteins (i.e., amino acid sequence). A new concep, however, has emerged of molecular mimicry that include the secondary and tertiary structures of proteins. In conformational diseases nonself molecular patterns can be afforded by the tertiary and quaternary structures of misfolded proteins. A modified self that exhibits new hydrophobic patches can be recognized as non-self by the immune system. Toll-like receptors (TLRs) play an essential role in the pathogenesis of autoimmune diseases. The exposed hydrophobic portions in proteins serve as endogenous ligands for receptors such as Toll-like receptors (TLRs) and others, activating them. The TLR4 itself has a large hydrophobic región and a variety of apparently unrelated molecules that signal through TLR4 have in common important hydrophobic regions.

Conclusions

From: Butnaru D, Chapman J. “The impact of self-replicating proteins on inflammation, autoimmunity and neurodegeneration-An untraveled path”. Autoimmun Rev. 2019 Mar;18(3):231-240

https://www.ncbi.nlm.nih.gov/pubmed/30639644

Background and Aims

To investigate the efficacy and possible mechanism of safflower yellow pigment (SY) on spleen cells in experimental autoimmune encephalomyelitis (EAE) mice.

Methods

Female C57BL/6 mice were induced with myelin oligodendrocyte glycoprotein 35-55 to establish an EAE model. Splenocytes were prepared on day 9 after immunization, and cultured with/ without safflower yellow pigment. The proliferation of splenocytes were detected by CCK-8 method and CFSE method. TNF-α, IL-1β, IFN-γ, IL-17 and IL-4 in the supernatant were detected by ELISA. Flow cytometry was used to detect the changes of M1 and M2 macrophage phenotypes, and the Griess method was used to detect the NO content in the supernatant.

Results

When the concentration of SY was 26.24mg/L, the proliferation rate of spleen cells could be increased (P<0.01), and the inflammatory factors TNF-α, IL-1β, IFN-γ, IL-17 were inhibited and the expression of antiinflammatory factor IL-4 in the supernatant were decreased (P<0.01). The ratio of proinflammatory macrophages in spleen was increased (P<0.01, P<0.05 respectively). NO content was decreased in the cultured supernatant (P<0.01).

Conclusions

The effectiveness of SY on spleen cells of EAE mice is related to the regulation of cytokine levels and the regulation of the ratio of proinflammatory and anti-inflammatory macrophages in the spleen. In addition, SY can also reduce the NO content. (Astragalus Resource Industrialization and Industrial Internationalization Cooperative Innovation Center Project of Shanxi Province, HQXTCXZX2016-028)

Background and Aims

Systemic lupus erythematosus in children younger than 18 years of age is known as Juvenile systemic lupus erythematosus (JSLE). Depression and anxiety are not well understood in JSLE. We investigated the clinical and psychological factors associated with depression and anxiety in JSLE.

Methods

Twenty-nine JSLE patients were recruited for the study. They were given a variety of surveys to test their psychological status and perceptions about their health, including the Hospital Anxiety and Depression scale, the Fatigue Severity Scale, and a Medical outcomes questionnaire (the SF-36). Multiple clinical lab test results were obtained from the patients’ medical records. Univariate and Multivariate analyses were used to compare the patient populations with Adult-onset SLE (ASLE) patients and unaffected controls, and find indicators that correlated with depression and anxiety in JSLE patients.

Results

Kidney disease was associated with depression in the JSLE patients. BUN , BUN/creatinine ratio, and leukocyturia were all significantly associated with depressive symptoms. The BUN/creatinine ratio was the most predictive value for both depression and anxiety.The JSLE patients had less depression than the ASLE, although anxiety was similar. Age and education were protective against depression in the JSLE patients. Psychosocial factors that correlated with depressive symptoms in the JSLE patients included fatigue, pain, poor general health, and inability to perform social and physical roles.

Conclusions

Kidney function correlated with symptoms of depression and anxiety. This may mean that symptomatology is an important indicator of whether the patient needs psychiatric care. Age and education were likely protective against depression in the JSLE population.