Infections and Neuroimmune Disorders - PowerPoint Presentation

Slide1

Infections and Neuroimmune Disorders

Hayley Gans, MD

Stanford University Medical Center

Inflammatory Brain Disorder Conference

May 14th 2021

No conflicts of interest

Infections and central nervous system

Neurotrophic

Neuroinflammatory

Neuroinfection

& neuroimmunology is a growing sub-specialty of the nervous system.

Despite remarkable diagnostic and therapeutic advancements during the past 30 years through the prevention of infectious diseases by vaccine and the development of safe, effective antimicrobial agents,

neurologic infections remain a major cause of permanent neurologic disability worldwide.

Immune-system-to-brain communication

Klein and Hunter, Immunity 2017

Neurotrophic Pathogens

Neuroinvasive

and neurovirulent

Capable of disrupting the blood brain barrier (BBB) to enhance viral

neuroinvasion

Tat secretion from infected cells

promotes BBB opening through activation of cyclooxygenase 2 (COX-2), which in turn suppressed expression of tight junctions

stimulates MMP-9 in astrocytes, resulting in disruption of BBB integrity

Systemic inflammation disrupts BBB

Cytokines (TNF, IL-1

β,

type one interferons) modulate BBB integrity through

differential regulation of Rho GTPases in brain microvascular endothelial cells

Elevations in CAM expression which causes leukocyte extravasation and disrupts the integrity of the adhesion junctions

The induction of inflammatory events after microbial entry may prime the CNS to be more or less susceptible to the development of other diseasesPersistent infection and immune memory may allow for recurrent symptomsGenetic and epigenic effects of response to pathogens

CNS and systemic effects of neurotropic infections

Klein RS, et al, Annu Rev Immunol. 2019

Resident memory T cells (T

RM

) and antibody-secreting B cells within the CNS

Immunity following CNS infection is important for understanding long term CNS sequelae

Resident memory T cells TRM were discovered ~2009 and have been shown to be a fluid T cell subset with varying phenotypes and functionCNS privileged memory immune cells are thought to provide a protective function including TRMHowever, autoreactive and/or aberrantly activated TRM cells may be involved in the pathogenesis of autoimmune disordersAntibody-secreting B cells are independently regulated and have been linked to autoimmunity

Steinbach, et al. Science

Translational Medicine.

2019

Neuroimmunology

Neuroimmune disorders are a heterogeneous group of severe neurological conditions primarily characterized by inflammatory responses in the CNS

Distinct manifestations in childhood, adolescent and adulthood

Each entity rare but as a group are not uncommon

Heightened immune responses against the CNS

cell- mediated,

humorally

mediated, infection triggered and genetically defined mechanisms

Immune activity as causal or secondary is not fully understood

Unifying aspect is that the disease course can be modulated by immune- targeted therapies.

Wells, et al,

Nat Rev Neurol

14. 2018

Neuroimmune disorders

Acute disseminated encephalomyelitis (ADEM), acute flaccid myelitis (AFM),, neuromyelitis

optica

spectrum disorder (NMOSD), optic neuritis (ON), and transverse myelitis (TM), Guillain-Barré syndrome (GBS)

Antibodies against N-methyl-D-aspartate receptor (NMDAR), voltage-gated potassium channel complex proteins, glutamic acid decarboxylase acid,

gammaaminobutyric

acid (GABA) B, MOG antibody disease (MOGAD)

Neuroimmune disorders vs Infectious Encephalitis761 cases of encephalitisAnti-NMDAR encephalitis surpasses viral etiologies by as much as 4-foldDistinctive pattern vs infection:

preponderance of psychiatric symptoms, primarily psychosis with hallucinations and personality changecombination with EEG or MRI abnormalities that do not converge on the temporal lobelower levels of pleocytosis and protein content in the CSF

Gable et al. Clinical Infectious Diseases.

2012

Pillai et al, PEDIATRICS April 2015164 children

Infections Associated with Neuroimmune Disease

Anti-NMDA antibody induced encephalitis

herpes simplex virus

, varicella-zoster, Epstein-Barr, measles virus, mumps, group A hemolytic streptococcus, toxoplasma,

Chlamydophila pneumoniae

, 

Bordetella pertussis

, 

Bordetella

parapertussis

,

mycoplasma pneumoniae

ADEM

coronavirus, coxsackie, cytomegalovirus, Epstein-Barr, herpes simplex, hepatitis A, HIV, influenza, measles, rubella, varicella zoster, and West Nile virus. Other associated organisms associated include Borrelia burgdorferi, chlamydia, Leptospira, 

Mycoplasma pneumoniae

, rickettsia, and beta hemolytic StreptococcusGBSCampylobacter, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, and influenza-like illnesses, HIVPediatric acute-onset neuropsychiatric syndrome (PANS) or childhood acute neuropsychiatric symptoms (CANS)beta hemolytic Streptococcus: PANDASMycoplasma pneumoniae, influenza, Epstein-Barr virus, Lyme disease

MechanismSeveral broad immune phenomenonMolecular mimicrytrigger activation of autoreactive T lymphocytesEpitope spreading

Bystander activationSuperantigensreboot autoreactive T cells, thus inducing relapses

Acosta-Ampudia, et al. J Transl

Autoimmun. 2019

Sonar and Lal, Neuroimmune disease. 2019

Mechanisms

Immune activation against neuronal antigens

Involvement of both the autoantibodies and autoreactive T cells

Strong association of human leukocyte antigen (HLA) polymorphism supporting role for both CD4 and CD8 T cells

Pathogen-derived molecules show molecular mimicry to the myelin and other CNS antigens

L2 protein of human papillomavirus 7, DNA polymerase of EBV and HSV, and hemagglutinin of influenza virus mimic human MBP85–99 epitope

DNA polymerase of HBV mimics human MBP66–75

Human CMV capsid protein UL86 981–1003 mimics the rat MOG

immunodominant glycoproteins of

C.

jejuni

,

lipooligosaccharides

(LOS), and lipopolysaccharide (LPS) closely resemble the neuronal gangliosides such as GM1, GD1a, GM1/GD1 complex and induce cross-reactive autoantibodies and effector T cells

M. pneumoniae and H. influenzae thought to cause GBS through the molecular mimicry of bacterial glycolipids with myelin galactocerebroside (Gal-C)group A β-hemolytic streptococcus (GABHS) : generates antibodies against epitopes on the basal ganglia

Mechanism

Interleukin-6 (IL-6), interleukin-17A (IL-17A), and C-X-C motif chemokine 13 (CXCL13) elevations

 negatively regulate the tight junction molecules, and prompt leukocyte migrating across the blood-brain barrier

Stimulate B cell differentiation, enhance the survival of

plasmablasts

, and promote antibody production

And IL-17A may trigger a positive-feedback loop for IL-6 signaling through signal transducer and activator of transcription 3 (STAT3) and nuclear factor (NF)-

κ

B

IL-17 promotes blood-brain barrier breakdown, IgG deposition, microglial activation, and loss of excitatory synaptic proteins

Initial infection may set up subsequent IL-17 expression from primed autoreactive T

h

17 cells during flare-ups caused by other pathogens including the influenza virus, mycoplasma, and staphylococcus aureus that are able to induce a robust T

h

17 cellular response.

PANDAS/PANS natural history

Prospective study in PANDAS patients; 40 matched case-controls

Initial diagnosis showed association of cases with GABHS

Exacerbations not associated with GABHS715 children with chronic tic disorder followed prospectivelyDid not detect any significant association of any of the 4 GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p

 values >0.3)Specific workup or active management of GAS infections is unlikely to help modify the course of tics in CTD and is therefore not recommendedProspective randomized study of 31 children with PANS receiving azithromycin or placebo for 4 weeks with standard neuropsychiatric medicationGreater reduction in the Clinical Global Impression-Severity Scale (CGI-S) for OCD symptoms in the azithromycin groupOther neuropsychiatric outcomes did not differ12 children with new-onset PANDAS followed for 3 yearsAll positive for GABHS and treated with resolution of symptoms

6 had recurrences, all positive and treated for GABHS with resolution

Kurlan

, Pediatrics. 2008

Martino et al, Neurology. 2021

Murphy et al, J Child

Adolesc

Psychopharmacol

. 2017

Murphy and Pichichero, Arch Pediatr Adolesc Med. 2002

PANDAS and prophylaxis

40 children with PANDAS followed in an 8-mo. prospective, randomized cross-over trial of 4 months of prophylaxis

Equal number of infections in both the active and placebo phases of the study.

There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases.23 children with PANDAS followed for a year, randomized, double-blind studySignificant decreases in streptococcal infections and neuropsychiatric exacerbations during the study year compared with baseline year

Garvey, et al: Biol Psychiatry. 1999Snider, et al: Biol Psychiatry. 2005

Is there a role for targeted therapy against infectionsAntimicrobial therapy should be administered if acute GABHS is identified to reduce the severity and duration of signs and symptoms of illness, including suppurative complications, reduce the incidence of nonsuppurative complications (eg, acute rheumatic fever), and reduce the risk of transmission

Burchi

. Prim Care Companion CNS Disord. 2018

Should Immunosuppression be delayedIs there risk for worsening a CNS infection if presentIn era of molecular diagnostics, potential to r/o infection in timely fashion does existCorticosteroids are of proven benefit when combined with anti- infectious therapies for the specific brain infections (pneumococcus, tuberculosis, HSV)HSV has been shown to reactivate

in vitro in the presence of dexamethasoneHSV induced anti- NMDA receptor encephalitis showed no viral reaction in the 93% who received immunosuppression and no anti-viral therapy

Wells, etc al. Nat Rev Neurol 14, 2018. PMID: 29925924

Immunotherapy for presumed Autoimmune Encephalopathy111 children 46% with identified autoantibodiesNo clinical, lab, or radiology differences between the groups with and without antibodiesImmunotherapy responsive disease in both groups

24% of group with autoantibodies had an identified infection (HSV, mycoplasma, EBV, Strep) but worsened despite targeted antiviral therapy but improved with immunotherapy

Hacohen. J Neurol Neurosurg Psychiatry. 2013. PMID: 23175854

Summary

Common pathway for infectious induced neuroimmune disorders is immune dysregulation

Molecular diagnostics may be helpful in ruling out infectious that would worsen with immunotherapy

While some entities may be ‘improved” with anti-microbial directed therapy, prospective, controlled studies in comparison to immunosuppression do not exist, and it is unclear if it is the immunosuppressive qualities of antimicrobial therapy was the effective therapeutic

Acute infections should be treated

Early effective immunosuppression is associated with better long-term prognosis; thus, delay is not substantiated by the potential infectious risk if autoimmune disease is substantiated

Specific immune abnormalities are hall marks of different neuroimmune disorders that may direct immunotherapy modalities which requires

Questions

Thanks

1. Klein RS, Hunter CA. Protective and Pathological Immunity during Central Nervous System Infections.

Immunity. 2017;46(6):891-909.

2. Klein RS, Garber C, Funk KE, et al. Neuroinflammation During RNA Viral Infections. Annual Review of Immunology. 2019;37(1):73-95.3. Sonar SA, Lal G. Overview of Mechanisms Underlying Neuroimmune Diseases. In: Springer International Publishing; 2019:3-62.

4. Steinbach K,

Vincenti I, Egervari K, et al. Brain-resident memory T cells generated early in life predispose to autoimmune disease in mice.

Science Translational Medicine.

2019;11(498):eaav5519.

5. Wells E, Hacohen Y, Waldman A, et al. Neuroimmune disorders of the central nervous system in children in the molecular era.

Nature Reviews Neurology.

2018;14(7):433-445.

6. Acosta-

Ampudia

Y, Monsalve DM, Ramirez-Santana C. Identifying the culprits in neurological autoimmune diseases.

J

Transl Autoimmun

. 2019;2:100015.7. Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis. 2012;54(7):899-904.8. Pillai SC, Hacohen Y, Tantsis E, et al. Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome. Pediatrics. 2015;135(4):e974-984.9. Kurlan R, Johnson D, Kaplan EL. Streptococcal Infection and Exacerbations of Childhood Tics and Obsessive-Compulsive Symptoms: A Prospective Blinded Cohort Study.

PEDIATRICS. 2008;121(6):1188-1197.10. Martino D, Schrag A,

Anastasiou Z, et al. Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders. Neurology.

2021;96(12):e1680-e1693.

11. Murphy ML,

Pichichero

ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS).

Arch Pediatr

Adolesc

Med.

2002;156(4):356-361.

12. Murphy TK, Brennan EM,

Johnco

C, et al. A Double-Blind Randomized Placebo-Controlled Pilot Study of Azithromycin in Youth with Acute-Onset Obsessive–Compulsive Disorder.

Journal of Child and Adolescent Psychopharmacology.

2017;27(7):640-651.

13. Garvey MA, Perlmutter SJ, Allen AJ, et al. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections.

Biol Psychiatry.

1999;45(12):1564-1571.

14. Snider LA,

Lougee

L, Slattery M, Grant P, Swedo SE. Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders.

Biol Psychiatry.

2005;57(7):788-792.

15.

Burchi

E,

Pallanti

S. Antibiotics for PANDAS? Limited Evidence: Review and Putative Mechanisms of Action.

Prim Care Companion CNS

Disord

.

2018;20(3).

16. Hacohen Y, Wright S, Waters P, et al.

Paediatric

autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens.

Journal of Neurology, Neurosurgery & Psychiatry.

2013;84(7):748-755

.