6: Chronic Inflammation, Tolerance, Autoimmunity

autoimmunity

immune system (humoral or T-cell mediated) attacks self tissues

self tolerance & subtypes

differentiation of self vs foreign

central tolerance: elimination of auto-reactive cells in primary lymphoid organs

peripheral tolerance: elimination auto-reactive and commensal microorganism-reactive cells in secondary-lymphoid organs

immune evasion

hiding antigens from immune system in immune-privileged sites

immune elimination

self-reactive lymphocytes are deleted before they can do damage

immune engagement

immune system maintains self-reactive populations (TREGs) for long term protection of self

immune-privileged sites; definition & why do they exist? what is a con they have?

area with minimal immune cells and minimal lymphatic vessels

sequestering antigens away from immune cells avoids self-reactivity

con: antigens aren’t part of peripheral tolerance pathways, so if an infection occurs, may have extra inflammation (since antigens there haven’t gone through peripheral tolerance)

Negative Selection in thymus

if a T-cell precursor binds to self-peptide with high affinity, it either dies by apoptosis or becomes a TREG

How do TREGs prevent effector T-cell activation?

• TREG TCR binds to self-antigen on MHC-II of DC

• TREG CTLA-4 (high concentration) binds to CD80/86 (blocks effector T-cell CD28) → induces release of immunosuppressive cytokines (IL-10, TGF-B, IL-35)

• TREG CTLA-4 down-regulates/inhibits DC’s MHC-II & production of inflammatory cytokines

• TREG IL-2R = IL-2 (proliferation) sink, prevents growth factor from reaching effector T cells

autoimmunity

failure of tolerance processes

Hashimoto’s Thyroiditis; how does it work & how is it treated

(organ-specific autoimmunity)

• Auto-antibodies activate TH1 cells specific for thyroid antigen → binding stops iodine uptake → thyroid function decrease → hypothyroidism

• Tertiary lymphoid organ forms in thyroid → Induces DTH response (b/c TH1 activated) → macrophages damage thyroid gland and further decreases thyroid function

Treatment: daily thyroxine

T1DM; how does it work & how is it treated

(organ-specific autoimmunity)

• auto-antibodies bind beta cells → induce antibody-mediated complement lysis or ADCC → decreased insulin production, increased BG → DTH response: CTL and macrophages infiltrate pancreas and cause inflammation

• dysregulation of glucose causes metabolic problems

Treatment: daily insulin admin

systemic autoimmunity

auto-reactive cells recognize self-antigens as foreign in multiple tissues/organs

systemic lupus erythematosus (SLE); definition and what are some examples?

(systemic autoimmunity)

SLE auto-antibodies produced against cells/common cellular components

• RBC and platelet-specific auto-antibodies → complement-mediated lysis → hemolytic anemia (RBCs), thrombocytopenia (platelets)

Immune complexes form w/ antigens on small blood vessel walls → type III hypersensitivity reaction (inflammatory damage to BV walls, high amounts of complement lead to neutrophils)

Multiple Sclerosis (MS)

(systemic autoimmunity)

Autoreactive CD4 TH17 cells → secrete IL-17 (neutrophil activation, pro-inflammatory response) → promotes inflammation at myelin sheath → breakdown of myelin leads to neurological dysfunction

Rheumatoid Arthritis (RA)

(systemic autoimmunity)

antibodies react w/ citrullinated AAs and RFs (auto-antibodies, usually IgM) → RFs bind to IgG → immune complex (citrullinated AAs + IgE + IgM) → activate complement & induce type III hypersensitivity, chronic inflammation

What TH cell subtype (and its cytokine) have a major role in autoimmunity?

TH17 cells and IL-17

IFN-gamma (potent activator of CTLs)

Types of treatment for autoimmunity treatment

1. Broad-spectrum therapies

2. Strategies targeting specific cells

3. Therapies blocking inflammatory process

Broad-Spectrum autoimmunity treatment

Suppress lymphocyte survival/proliferation, kill rapidly dividing cells

includes: corticosteroids, azathioprine, cyclophosphamide, methotrexate

SEs: cytotoxicity to any rapidly dividing cells, increased risk of infection/cancer (immunocompromised)

strategies targeting specific cells for autoimmunity treatment

rituximab: mAB that binds CD20 on B-cells → depletes subset of B-cells; short-term benefit in RA

OKT3: mAB that binds to CD3 (on TCR) → depletes T cells; partially effective against TD1

• induces strong immune suppression

therapies blocking inflammatory process for autoimmunity treatment

1. drugs that block TNF-a (used for RA)

2. IL-1 (major pro-inflammatory cytokine) antagonist (used for RA)

3. mABs to IL-6R (B-cell differentiation), IL-2R (T-cell proliferation), IFN

4. statins (reduce CRP) inhibit proclamatory cytokines (RA, MS symptoms)

5. Fingolimod inhibits cell trafficking (adhesion molecules, chemokines) → can’t leave primary lymphoid organs

chronic inflammation

persistent, increased expression of inflammatory cytokines (even with no major infection)

infectious causes of chronic inflammation

• pathogen with continuous access to the body

• failed protection from commensal bacteria in gut (disruption by antibiotics)

• pathogens evade immune system and cause low-level inflammatory reactions

• fungi, mycobacteria not completely cleared

noninfectious causes of chronic inflammation

• damage to tissue → releases DAMPs → secretion of inflammatory cytokines

• tissue damage not completely resolved

• tumors, autoimmunity, artherosclerosis/heart disease, alzheimer’s

how does obesity cause chronic inflammation

intracellular stress responses from excessive lipid buildup → visceral adipocytes secrete pro-inflammatory cytokines (TNF-a, IL-6) → recruit macrophages to adipose tissue

free fatty acids bind TLRs on adipocytes → induce cytokine release

Why is T2DM a long-term consequence of chronic inflammation?

excess lipids → inflammatory cytokines (TNF-a, IL-6) released by visceral adipocytes → prevent insulin receptor from activating downstream events → failure of cells to respond to insulin → T2DM