IMM SS25 Talks – Viruses and Autoimmunity

Viruses and Autoimmunity

Viral Mechanisms Causing Autoimmune Diseases (AID)

• Presenting self-antigens to autoreactive T cells:
  • Antigen-presenting cells (APCs) present self-antigens to autoreactive T cells, triggering an immune response against the body's own tissues.
• Molecular mimicry:
  • T cell receptors (TCRs) on cytotoxic T lymphocytes (CTLs) recognize viral antigens that share structural homology with self-antigens.
  • This leads to the activation of CTLs, which then attack cells displaying the self-antigens.
• Bystander activation:
  • Viral infections can cause cell damage and the release of self-antigens.
  • This triggers an immune response involving the release of cytokines, activation of T cells (both CD4+ and CD8+), and the production of perforin/granzymes, leading to further cell damage.
• Epitope spreading:
  • Immune responses against viral epitopes can spread to self-epitopes, resulting in an autoimmune response.
  • This involves uninfected cells being targeted due to their expression of self-antigens.

Multiple Sclerosis (MS)

• Symptoms:
  • Fatigue, cognitive impairment, depression, anxiety, unstable mood (central).
  • Nystagmus, optic neuritis, diplopia (visual).
  • Dysarthria, dysphagia (throat/speech).
  • Weakness, spasms, ataxia (musculoskeletal).
  • Pain, hypoesthesias, paraesthesias (sensation).
  • Incontinence, diarrhea, or constipation (bowel).
  • Incontinence, frequency, or retention (urinary).
• Pathogenesis:
  • Destruction of the myelin sheath, which impairs nerve signal transmission.
• Diagnosis and treatment:
  • Immune modulators (monoclonals, interferon, small molecules), corticosteroids, symptomatic treatment.
• Epidemiology:
  • More common in women (3:1 ratio).

Systemic Lupus Erythematosus (SLE)

• Symptoms:
  • Low-grade fever, photosensitivity (systemic).
  • Ulcers in the mouth and nose.
  • Muscle aches.
  • Fatigue, loss of appetite (psychological).
  • Butterfly rash on the face.
  • Arthritis (joints).
  • Inflammation of the pleura and pericardium.
  • Kidney inflammation.
  • Poor circulation in fingers and toes.
• Pathogenesis:
  • Production of anti-nuclear autoantibodies.
  • Immune complex deposition in various organs.
• Diagnosis and treatment:
  • Hydroxychloroquine, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, immunosuppressants (small molecules).
  • Monoclonal antibodies against B-cell activation
• Epidemiology:
  • 90% women, higher prevalence in Hispanic, Black, and Asian people.

Hydroxychloroquine

• Increases pH within intracellular vacuoles.
• Alters protein degradation by acidic hydrolases in the lysosome.
• Affects the assembly of macromolecules in the endosomes.
• Impacts post-translational modification of proteins in the Golgi apparatus.
• Immunomodulatory effects, including inhibition of cytokine release.
• In Plasmodium, it inhibits the breakdown of toxic heme in the food vacuole, leading to lysis of Plasmodium.

Diabetes I

• Pathogenesis:
  • Destruction of beta cells in the pancreas.
• Diagnosis and treatment:
  • Insulin, lifestyle management, symptomatic treatment.
• Epidemiology:
  • Bit higher incidence in men.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Etiology:
  • Association with viral infections.
• Symptoms:

Otosclerosis

• Symptoms:
  • Stapes blocked.
• Diagnosis and treatment:
  • Hearing aids, surgery.
• Epidemiology:
  • Higher incidence in women (2/3 female).

Epstein-Barr Virus (EBV)

• Type: Herpesvirus HHV4
• Transmission: Saliva, droplets, sexual contact
• Course of infection and symptoms: Infectious mononucleosis
• Genome: dsDNA, enveloped
• Vaccine: No vaccine
• Latency: Latency in B-cells
• Life Cycle: Can infect epithelial cells

EBV and Multiple Sclerosis

• 95% infection rate, but MS is rare.
• Risk factors for MS: genetic susceptibility, environmental factors, lack of sun exposure and vitamin D, smoking, and obesity.
• EBV modulates immune response.

US Military Blood Samples Study:

• Over 10 million persons over 20 years old.
• 5.3% negative for EBV in the first sample.
• 955 developed MS.
• Risk for MS increased 32x after EBV infection.

EBV and Lupus Erythematosus

• EBV is one of the viruses that can trigger lupus.
• Causes dysregulation of the immune system and autoantibodies.

EBV and Cancer

• EBV establishes lifelong persistence in B cells.
• Intrinsic factors (e.g., genetic mutations) and extrinsic factors (e.g., immunosuppression, HIV infection, diet) can result in EBV-associated cancers.

CAR-T Cell Therapy

Principle of CAR-T Cell Therapy Against Cancer

CAR-T Cell Therapy Against Lupus

• Works in clinical studies.

Measles

• Type: Paramyxoviridiae family - Morbillivirus genus
• Genome: ss RNA (-), enveloped, 120 to 250 nm
• Natural host: Humans
• Transmission: Aerosols, highly infectious
• Vaccine: MMR/V vaccine, life-attenuated
• Symptoms: Koplik spots, Measles rash

Measles - Severe Complications

• Pneumonia (1 in 20 children).
• Encephalitis (1 in 1,000 children), leading to convulsions, deafness, or intellectual disability.
• Death (1 to 3 of every 1,000 children) from respiratory and neurologic complications.
• Complications during pregnancy: premature birth or low-birth-weight baby.

Measles - Long Term Effects

• Immunosuppression, leading to Pneumonia and Bronchitis
• Pregnancy Complications
• SSPE (Subacute Sclerosis Encephalitis):
  • Progressive neurodegenerative disorder.
  • CNS scarring → vision loss, seizures, cognitive decline.
  • Measles infection under 2 years → SSPE after 7-10 years.
  • 1990s: 9/100,000 developed SSPE.
  • Fatal

Measles Virus Infection and Transmission

• The measles virus (MeV) is an airborne pathogen.
• It infects alveolar macrophages or dendritic cells (DCs) in the respiratory tract using signaling lymphocytic activation molecule (SLAM; CD150) as a receptor.
• Infection amplifies in lymphoid tissues, leading to systemic infection.
• MeV-infected lymphocytes and DCs transmit MeV to epithelial cells via nectin 4 as a receptor.
• Progeny viruses are released into the respiratory tract.
• Key proteins: Nucleocapsid protein (N, NP), Large polymerase (L), Phosphoprotein (P), Attachment protein (HN, H, G), Lipid Envelope, Matrix protein (M), Fusion protein (F)

Measles History

• Evolved from an ancestral virus and emerged as a zoonotic infection.
• Established in humans about 5,000 years ago.
• Entered the Americas in the fifteenth century.
• Measles outbreak in the US Army from 1917 to 1918 resulted in >95,000 cases and 3,000 deaths.
• Increasing measles vaccine coverage prevented an estimated 17.1 million deaths between 2000 and 2014.
• Closely related to the recently eradicated cattle virus rinderpest.
• Measles virus and rinderpest virus divergence dated to the sixth century BCE.

Parameters for Virus Eradication

Measles Oncolytic Therapy

• Some cancers overexpress the receptor CD46 used by the attenuated measles vaccine virus and have reduced the cellular immune response
• Attenuated Virus replicates
• A dying tumor cells, neutrophils, macrophages, and activated DCs lead to T cell infiltration and effector response.
• Genetically engineered measles viruses:
  • Targeting: other receptors.
  • Silencing cancer genes.
  • Arming.
  • Stealthing.

Measles and Otosclerosis

• Stapes cannot transmit sound, leading to hearing loss.
• Possible reasons: genetics, viral infections (measles), hormones (2/3 female).
• Anti-measles IgG in perilymph.
• Less cases in vaccinated persons.
• Some studies find measles RNA in stapes.

Rubella

• Type: Matonaviridae family – Rubivirus genus
• Genome: ss RNA (+), enveloped, 40 to 80 nm
• Transmission: Aerosols/via placenta
• Vaccine: MMR/V vaccine: life attenuated

Rubella Virus Life Cycle

• Virus binds to plasma membrane receptors and enters the host cell by clathrin-mediated endocytosis.
• Low pH and Ca^{2+} activate virus membrane fusion in the early endosome.
• The genomic RNA is translated to the nonstructural polyprotein p200, which synthesizes negative-strand RNAs.
• Transcription of positive polarity genomic and subgenomic RNAs takes place.
• The structural polyprotein precursor p110 is translated from subgenomic RNA and translocated into the ER.
• The capsid assembles with genomic RNA into NC on the RER and then is transported to the Golgi by interactions with E2 and/or the E2-E1 dimer.
• E2-E1 heterodimers are transported to the Golgi, where RUBV assembly and budding take place.
• Transport vesicles deliver mature RUBV from the Golgi to the cell surface.

Rubella Symptoms

• Adults/Children
  • Skin rash.
  • Mild fever.
  • Coughing/Sneezing.
  • Rhinitis (runny nose).
  • Swollen lymph nodes.
  • Joint pain.
• Possible complications: Brain inflammation, heart inflammation, pneumonia, low platelet count.
• After encountering the disease, a person usually develops lifelong immunity.

Rubella in Pregnancy

• 90% of babies can be born with Congenital Rubella Syndrome (CRS).
• CRS can lead to deafness, cataracts, learning disabilities, etc.
• Severe consequences on the development of the baby's organs.
• 20% of the pregnancies can result in spontaneous abortion and stillbirth/fetal death.
• Affect 85 out of 100 babies.
• Deafness remains a risk until 20 weeks.

Rubella Vaccines

• Estimated Current and Future Congenital Rubella Syndrome Incidence with and Without Rubella Vaccine Introduction — 19 Countries, 2019–2055

Rubella and Diabetes I?

• Diabetogenic viruses such as Coxsackie A virus (CAV), coxsackie B virus (CBV), echovirus (ECV), rubella virus (RuV), cytomegalovirus (CMV), mumps (MuV) and rotavirus (RoV) are known to have tropism to β-cell and are therefore classified as diabetogenic viruses.
• Infection of b-cells + genetics