Understanding Autoimmunity

• Autoimmunity is when the immune system attacks the body's own healthy cells, tissues, and normal constituents.

History of Autoimmunity

• Paul Ehrlich predicted autoimmunity in the early 20th century, describing it as "horror autotoxicus," or "fear of self-destruction."

Definition of Autoimmunity

• Autoimmunity includes abnormal immune responses against self-antigens.

Immune System Involvement

• Any arm of the immune system, including both innate and adaptive immunity, can be involved in autoimmunity.
• Innate immunity involves a non-specific, general immediate response with limited immunological memory.
• Adaptive immunity is specific to an antigen, with a lag time from exposure to the response but has long-term immunological memory.

How the Body Prevents Autoimmunity

• Central Tolerance: Negative selection of self-reactive T and B cells.
• Peripheral Tolerance: Ensures that self-reactive T cells that escape into the periphery are deleted or become anergic (functionally unresponsive).

T cell receptor

• T-Cells: Reminder
• Immature CD4+ T cells recognize antigens presented by antigen-presenting cells via MHCII.
• They mature into helper T cells (Th1 or Th2).
• Immature CD8+ T cells recognize antigens presented by antigen-presenting cells via MHCI, becoming cytotoxic T cells (Tc).
• T cell receptor rearrangement involves recombination of gene segments to create diverse receptors.
• T cell receptor selection includes somatic rearrangement of TCR and positive and negative selection in the thymus.
• mTEC(medullary thymic epithelial cells) medullary thymic epithelial cells lead to prevention of autoimmunity.

B cell selection

• B cell selection: Immature B cells in the bone marrow undergo selection.
• Multivalent self-molecules lead to clonal deletion or receptor editing.
• Soluble self-molecules cause migration to the periphery and anergic B cells.
• Low-affinity noncross-linking self-molecules lead to migration to the periphery and clonally ignorant mature B cells.
• B cells need T helper cells for proper activation, involving interactions between peptide antigens, T cell receptors, and co-stimulatory molecules.
• Central tolerance involves negative selection of self-reactive T and B cells.
• Peripheral tolerance ensures self-reactive T cells are deleted or become anergic.
• Only professional APCs (Antigen-Presenting Cells) can prime T cells.
• Dendritic cells use chemokine receptors to stimulate T cells.
• T cell anergy occurs when T cells receive only signal 1, leading to tolerance or apoptosis.
• Regulatory T cells (Treg) suppress effector T cells.
• Treg can quantitative and/or functional deficiencies, Teff increases.
• Regulatory T cell (Treg) function is enhanced by IL-2, Adoptive Treg Therapy or anti-TNFa Therapy; Tregitope therapy.

Factors Contributing to Autoimmunity

• Genetic factors play a role, but single-gene mutations leading to autoimmune diseases are the exception.
• Autoimmune diseases are generally classified as complex diseases.
• Exceptions include APS-1 (AIRE), IPEX (FOXP3), and ALPS (FAS, FASL).
• Immunodeficieny too little
• Hypersensitivity too much
• Autoimmunity mis-directed

Effector Mechanism

• Treg effector mechanism: Treg effector mechanism is where Tregs release adenosine triphosphate by binding ATP, adenosine and trigger cell death through Granazyme B, TRAIL, galectin 9 Fas-L(Fas ligand) in addition to other functions.
• Sex differences exist in autoimmunity.
• The multifactorial nature of autoimmune diseases involves genetic susceptibility, gender, environmental triggers, and stochastic factors.
• The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.
• Autoimmune diseases are classified as complex diseases as there is not a single “pinpoint-able” gene

MHC pathways

• MHC-I/II pathway: reminder
• MHC class I pathway involves cytosolic proteins processed through proteasomes, presenting peptides via MHCI to CD8 T cells.
• MHC class II pathway involves extracellular proteins processed through endosomes, presenting peptides via MHCII to CD4 T cells.
• MHC polymorphism contributes to the diversity of immune responses.
• MHC Class 1 molecules includes HLA-A, B, and C
• MHC Class 2 molecules includes HLA-DR, DQ, and DP
• Certain MHC haplotypes are correlated with diabetes.

Breaking Tolerance

• Breaking tolerance includes mechanisms like disruption of cell barriers, molecular mimicry, and superantigens.
• Disruption of cell or tissue barrier releasing sequestered self-antigen, can lead to activation of nontolerized cells.
• Binding of pathogen to self protein causes pathogen will allow anti-self response.
• Infections can break tolerance, as seen in virus-induced diabetes in mice.
• Molecular mimicry: Molecular mimicry occurs when pathogen proteins resemble self proteins.
• Virus infection breaks tolerance by hybrid gene of LCMV nucleoprotein in pancreatic cells.

Release of antigen

• Release of sequestered or cryptic antigens leads to autoimmunity.
• Molecular mimicry: Rheumatic fever can occur group A streptococcus infections.

Pathogens

• Pathogens and molecular mimicry: certain pathogens cause immune reactions that can trigger autoimmune diseases via various mechanisms like molecular mimicry and the production of cross-reactive antibodies that affect the heart, nervous system, joints and the liver.

Autoimmunity Classification

• Autoimmunity is classified as organ-specific or systemic.
• Systemic affects many organs like rheumatoid arthritis.
• Organ-specific affects one organ.

Diseases

• Subtypes of autoimmune diseases: Type II involves antibodies against receptors or other self-proteins.
• Types III involves immune complex.
• Type IV involves T-Cell mediated.
• Myasthenia Gravis affects muscle activation.
• Rheumatoid occurs three to five times more often in women.
• Multiple Sclerosis is an inflammatory diseases which affects demyelination.

Autoimmunity Diagnosis

• Diagnosis is disease-dependent with no general rule.

Autoimmunity Treatment:

• Treatment: Take many forms. Treatment depends on the type of disease, how severe it, is, and its symptoms. the treatments have one of three goals:

Treatment of Autoimmunity

• Relieving symptoms: Relieving symptoms may simple as taking drugs for pain relief. can also be involved as having surgery
• Preserving organ function: treatment may be needed to prevent damage. Treatments include drugs to control kidney failure.
• Targeting mechanisms: target how the disease works with drugs that can suppress the immune system. These drugs may cause side effects.
• Autoimmunity therapy involves anti-inflammatory drugs, immunosuppressant drugs, radiation, plasmapheresis, and cell/cytokine blocking reagents.
• EAE (experimental autoimmune encephalomyelitis) is used in mice as a MS model for study.

Treatment details

• Non-steroidal anti-inflammatory drugs (Nsaids):
• Cox2-selective NSAIDs: Celecoxib, Rofecoxiba.
• Non-selective NSAIDs: Diclofenac, Ibuprofen, Naproxen.
• Coriticosteroids: are molecules that affect transactivation, mRNA and inflammation as examples.
• New therapies for Multiple sclerosis consist of injectable, Oral therapies for patients in many disease processes.

SLE

• SLE (Systemic lupus erythematosus): (Fig 1-3): Algorithm for the treatment of SLE. Short lived plasmablasts can be targeted and long-lived plasma cells do not respond to immunosuppressive and B cell depleting therapies