Interleukin 6: at the interface of human health and disease

Interleukin 6 (IL-6) is a pleiotropic cytokine executing a diverse number of functions, ranging from its effects on acute phase reactant pathways, B and T lymphocytes, blood brain barrier permeability, synovial inflammation, hematopoiesis, and embryonic development. This cytokine empowers the transition between innate and adaptive immune responses and helps recruit macrophages and lymphocytes to the sites of injury or infection. Given that IL-6 is involved both in the immune homeostasis and pathogenesis of several autoimmune diseases, research into therapeutic modulation of IL-6 axis resulted in the approval of a number of effective treatments for several autoimmune disorders like neuromyelitis optica spectrum disorder (NMOSD), rheumatoid arthritis, juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis (GCA), and cytokine release syndrome, associated with SARS-CoV2 pneumonia. This review discusses downstream inflammatory pathways of IL-6 expression and therapeutic applications of IL-6 blockade, currently investigated for the treatment of several other autoimmune conditions such as autoimmune encephalitis, autoimmune epilepsy, as well as myelin oligodendrocyte glycoprotein associated demyelination (MOGAD). This review further highlights the need for clinical trials to evaluate IL-6 blockade in disorders such neuropsychiatric lupus erythematosus (SLE), sarcoidosis and Behcet’s

The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and Species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction

Central nervous system blastomycosis presenting as a year-long chronic headache

This case describes a posterior fossa mass due to blastomycotic infection in a non-immunocompromised 41-year-old male presenting with a chronic headache for over one year. Given the risk of herniation, no lumbar puncture could be performed. A full work-up found no evidence of systemic infection. Surgical resection helped identify the mass as a blastomycotic abscess. Magnetic resonance imaging characteristics of the mass were helpful in the identification of the mass as a fungal abscess

The extracellular domain of myelin oligodendrocyte glycoprotein elicits atypical experimental autoimmune encephalomyelitis in rat and Macaque species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund"s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund"s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6--7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction

The Extracellular Domain of Myelin Oligodendrocyte Glycoprotein Elicits Atypical Experimental Autoimmune Encephalomyelitis in Rat and <i>Macaque</i> Species

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund’s adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund’s adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6–7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.</p

Booster immunizations with IgV-MOG in IFA caused a chronic course of atypical EAE.

<p>Seven Lewis rats were immunized with a mixture of 25 µg of GP69-88 and 50 µg of rat IgV-MOG in CFA on day 0. After resolution of a classical monophasic bout of EAE, the same rats were boosted with 200 µg of rat IgV-MOG in IFA on days 45 and 85. Rats were scored daily for clinical signs of EAE. After the IgV-MOG boosts in IFA, the incidence of chronic atypical EAE was 100% (7 of 7 rats). The red arrows (bottom panel) mark the dates of the boosts. Shown are the individual disease courses for the 7 rats. The blue line divides the clinical data into classical (left) and atypical (right) EAE courses.</p

A CFA/IFA prime-boost strategy with IgV-MOG elicited chronic atypical EAE in Lewis rats.

<p>Lewis rats were immunized with either 50 µg of GP69-88 or 200 µg of rat IgV-MOG in CFA on day 0. Rats were scored daily for clinical signs of EAE. On day 28, GP69-88-immunized rats were or were not boosted with 50 µg of GP69-88 in IFA. Conversely, rat IgV-MOG-immunized rats were or were not boosted with 200 µg of rat IgV-MOG in IFA. Shown are overlapping traces of disease courses of rats immunized with GP69-88 (A), immunized with GP69-88 and given a subsequent boost (B), or immunized with rat IgV-MOG without a subsequent boost (C). Also shown are atypical disease courses of individual rats immunized and boosted with rat IgV-MOG (D–F; 3 of 4 rats shown). Red arrows indicate the booster immunization (B, D–F). The blue line divides the clinical data into classical (left) and atypical (right) courses (D–F).</p

The isotype of the macaca anti-MOG Ab was IgG.

<p>Shown are GFP⁻ non-transfected HEK (A) or GFP⁺ macaca MOG HEK (B–F) that were stained with macaca serum collected on days 0, 22, 36, 49, or 63 (A–E) and 93, 210, 469, or 730 (F) post-immunization as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110048#pone-0110048-t001" target="_blank">Table 1</a>. HEK were subsequently stained with an allophycocyanin-conjugated secondary Ab specific for macaca Ab isotypes, including anti-IgG/M/A (A–B), anti-IgG (C, F), anti-IgM (D), anti-IgA (E).</p

Lewis rats immunized with IgV-MOG developed Ab specific for conformational epitopes of MOG.

<p>(A) Lewis rats were immunized with IgV-MOG in CFA, boosted with IgV-MOG in IFA, and sera were taken on day 75. Clinical courses of donor rats are shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110048#pone-0110048-g001" target="_blank">Figure 1</a> (numbered 1–7 top to bottom). Shown are GFP⁺-gated rat MOG HEK cells stained with: Black trace = normal rat serum; Blue trace = rat #2 with clinical score of 0; Red trace = rat #1 with clinical score of 1.0; Green trace = rat #3 with score of 3.0. (B) Lewis rats were immunized with IgV-MOG in IFA via the same antigens and schedule as designated for the NHP in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110048#pone-0110048-t001" target="_blank">Table 1</a>. These rats (n = 3) did not exhibit clinically evident EAE. Shown are histograms of GFP⁺-gated rat MOG HEK cells labeled with normal rat serum (black trace) or immune serum from two separate asymptomatic rats (red versus blue) taken 442, 116, 416, and 93 days (top to bottom) after the day of immunization (DOI). Shaded traces indicate at least one year since DOI. Labeled cells were detected with an allophycocyanin-conjugated secondary goat-anti-rat IgG/M secondary Ab. Analyses were of individual serum samples, not pooled sera.</p