autoimmunity and hypersensitivity

In Brief: Hypersensitivity is…

• Excessive or inappropriate immune response to antigens

• Can be towards harmless foreign antigens (allergy, microbiota) or self (autoimmunity)

• Classified as Type I – IV

allergies vs autoimmunities

hypersensitivity can be towards harmless foreign antigens (allergy, microbiota) or self (autoimmunity)

In Brief: Autoimmunity

• Type of hypersensitivity

• Immune response against self-antigens

• Failure of tolerance mechanisms - usually to self antigens, highly reactive T cells are aoptosed in negative selection 

• Leads to chronic inflammation, tissue injury

• Involves innate and adaptive immunity

Timeline of an antibody-driven immune response - explain the graph

autoimmune response - antibodies are produced against a self-antigen

antibodies fail to return to low/initial levels after the initial response → chronic inflammation and ongoing tissue damage 

Predisposing & Precipitating Factors to autoimmunity

• Genetic: HLA associations (e.g., HLA-DR4 in RA)

• Sex: Higher in females (hormonal, genetic factors)

• Environmental: Infections, smoking, UV light, diet

• Precipitating events: Trauma, stress, infection

autoimmunity - overview steps 5

1. loss of central tolerance

2. defects in peripheral tolerance 

3. environmental triggers/precipitating events 

4. activation of autoreactive lymphocytes 

5. amplification and chronic inflammation 

Autoimmunity - Step 1: Loss of Central Tolerance

Central tolerance normally eliminates autoreactive T and B cells in the thymus and bone marrow. => If elimination is incomplete, autoreactive lymphocytes escape into circulation.

Mechanisms that normally keep escaped autoreactive cells under control: 3 

1. Anergy: autoreactive lymphocytes fail to activate → lost.

2. Regulatory T cells (Tregs): suppress autoreactive responses.

3. Deletion (apoptosis): elimination of activated autoreactive cells.

Autoimmunity - Step 2: Defects in Peripheral Tolerance (back up mechanism)

Mechanisms that normally keep escaped autoreactive cells under control:

1. Anergy: autoreactive lymphocytes fail to activate → lost.

2. Regulatory T cells (Tregs): fail to suppress autoreactive responses.

3. Deletion (apoptosis): defective elimination of activated autoreactive cells.

Failure of peripheral tolerance => autoreactive lymphocytes can survive in the tissues

Autoimmunity - Step 3: Environmental Triggers / Initiating Events

• External factors provide the “spark” that activates autoreactive cells:

1. Infections (molecular mimicry, bystander activation) — e.g., rheumatic fever after Streptococcus infection.

2. Tissue damage — release of normally hidden (“sequestered”) antigens.

3. Drugs, toxins, UV light — can alter self-antigens, making them appear foreign.

Autoimmunity - Step 4: Activation of Autoreactive Lymphocytes

• Under the influence of costimulatory signals - like TCR binding to MHC (from infection or inflammation), autoreactive T or B cells become activated.

• These cells start producing pro-inflammatory cytokines or autoantibodies.

Autoimmunity - Step 5: Amplification and Chronic Inflammation

• Once initiated, the immune response becomes selfperpetuating:

• Autoantigens are continuously released from damaged tissue.

• This provides new targets for immune attack, creating a vicious cycle

• Chronic inflammation leads to progressive tissue damage and clinical disease.

Normal vs Autoimmune Responses

autoimmunity - Incidence & Impact

• Affects ~10% of population in the UK (Conrad et al., Lancet 2023)

• Chronic, relapsing conditions without cure → increasing burden

• Higher prevalence in women (~1.75:1 ratio)

Sex-Divergence in Autoimmunity

Majority of autoimmune disorders are more common in women Reasons:

• Estrogen enhances (autoreactive) B cell survival & antibody production

• X-chromosome genes (e.g., TLR7 duplication in SLE)

• Pregnancy/hormonal shifts modulate disease activity

Organ-Specific Autoimmune Diseases - 3

affect a particular organ or tissue type, with localised damage and dysfunction

1. Type 1 diabetes - immune system attacks the insulin-producing beta cells in the pancreas - typically develops in childhood or adolescence - genetic factors (e.g., HLA-DR3 and DR4 alleles) & environmental triggers (e.g., viral infections

2. Multiple sclerosis - affects the central nervous system (CNS) - immune system targets the myelin sheath of nerve fibres - often begins in early adulthood- muscle weakness, vision problems and co-ordination issues 

3. Hashimoto’s thyroiditis - common cause of hypothyroidism (underactive thyroid) - immune system attacks the thyroid gland, impairing hormone production - tends to run in families, i.e. genetic factors are likely involved - fatigue, weight gain. cold intolerance and depression 

Organ-Specific Autoimmune Diseases - diagnosis and treatment 

• Autoimmune responses can cause very targeted damage of organs, despite the immune system’s systemic role in protecting the body.

• Diagnosis often involves detecting autoantibodies specific to the affected organ and using imaging or functional tests to assess organ damage.

• Treatments to reduce inflammation, manage symptoms, replace lost function (e.g., insulin therapy in T1D or thyroid hormone replacement in Hashimoto’s).

• Major side effect: immunosuppression

Systemic Autoimmune Diseases - 3

affect multiple organs and tissues throughout the body

1. Sjögren’s syndrome -autoimmune responses attack salivary and tear glands, leading to dry mouth and dry eyes. -involves multiple organs (lungs, kidneys, liver) nervous system -arises from a combination of genetic susceptibility and environmental triggers - fatigue, joint pain and swelling of the salivary glands

2. Systemic lupus erythematosus (SLE) - autoantibodies form immune complexes that deposit in tissues (skin, kidneys, joints, blood vessels) and trigger inflammation & tissue damage - disproportionately affects women, particularly during reproductive years - caused by combination of genetic susceptibility, hormones & environmental factors - joint pain, fatigue, rash

3. Rheumatoid arthritis (RA) - primarily affects the lining of the joints/synovium, leading to chronic inflammation, pain, swelling, and eventual joint destruction - also affects other organs, including the lungs, heart, and blood vessels - influenced by genetic and environmental factors (e.g. smoking) - fatigue, amenia and nodules under the skin

Mechanisms in SLE - TLRs and B Cells

• TLR receptors that usually detect bacterial/viruses become activated when they encounter self-nucleic acids when they encounter dying cells

• autoreactive B cells produce large amounts of  autoantibodies 

• autoimmune complexes depositing in the skin 

• autoreactive B cells also act as APC - capture self antigens MHC II - activate autoreactive T cells 

Mechanisms in RA - complex interplay of genetics, immune dysregulation, and microbiota 4

1. Joint Pathology - Autoimmune responses targets the synovium resulting in pannus formation (abnormal fibrovascular tissue), joint deformity & loss of function

2. joint pain lasting more than 1 hour- symmetrical joint pain and swelling 

3. Genetic Factors - HLA-DR4 / HLA-DRB1 shared epitope alleles influence antigen presentation

4. Autoantibodies - Rheumatoid Factor (RF): antibody against Fc portion of IgG - Anti-CCP antibodies: highly specific, appear years before symptoms

5. Immune Cell Contributions

• CD4+ T cells: release cytokines (TNF-α, IL-1, IL-6) that drive inflammation

• B cells: produce autoantibodies & act as antigen-presenting cells

• Macrophages: amplify cytokine production

• Osteoclasts: mediate bone erosion

Mechanisms in RA → Microbiota Link

• Microbial dysbiosis may trigger autoimmunity in genetically predisposed individuals

• Gut microbe Segatella copri (prev. Prevotella copri), oral bacteria (e.g. Porphyromonas gingivalis) are associated with RA

• Porphyromonas gingivalis (perio) induced protein citrullination generates antigens of cross-reactive auto-reactive antibodies (ACPA) - unique enzyme in P gingivalis can modify host proteins in a specific manner - citrillation - generates antigens targeted by CCP antibodies - drives RA 

• P. gingivalis impairs mucosal barrier function -> exacerbation of systemic inflammation

Comorbidities in systemic autoimmune diseases

• Individuals with any autoinflammatory disease: increased risk for other comorbidities

• Treatment: target multiple organs & systems simultaneously, while preserving functions of protective immune responses & other body functions 

Hypersensitivity - how many types are there?

4 

• 1 - immediate IgE mediated allergy

• 2 - antibody mediated cytotoxicity

• 3- immune complex diseases - RA, SLE

• 4- T cell mediated delayed response - contact derm T1D

Hypersensitivity - Type I - overview and examples

• Mediated by IgE bound to high-affinity Fc receptors on mast cells, basophils, and eosinophils

• Antigen cross-linking causes rapid degranulation (minutes)

• Release of histamine, serotonin, leukotrienes, proteases

• early and late phase

• Examples: allergies (hay fever, asthma, food allergy);

not organ specific

hypersensitivity type 1 early phase  3

(minutes)

Early phase effects (minutes):

1. increased vascular permeability

2. Smooth muscle contraction,

3. bronchoconstriction

swelling, itching and wheezing

hypersensitivity type 1 late phase (hours)

Late phase (hours):

cytokine release → recruitment of eosinophils, neutrophils, macrophages

extreme reaction = anaphylactic shock

Hypersensitivity - Type II (2-24h)

• antibody mediated 

• Mediated by IgG (IgG1, IgG2, IgG3) binding to antigens on cell or tissue surfaces

• - Effector mechanisms:

• IgG Fc binds Fcγ receptors on macrophages & NK cells → cytotoxicity

• IgG activates complement → opsonisation & phagocyte recruitment

• Outcome: degranulation or phagocytosis, causing tissue damage

• Typically organ-specific (selfantigen on target tissue)

Examples: autoimmune hemolyticanemia, Goodpasture’s syndrome, myasthenia gravis

Hypersensitivity - Type III (hours-days)

• immune complex

• Mediated by IgG binding to soluble antigens → immune complex formation -

• normally cleared but can acculate - Deposition of complexes in blood vessels, joints (synovial fluid), and other tissues -

• Complement activation → release of C3a, C5a (inflammation, chemotaxis) -

• Recruitment of neutrophils & macrophages via Fc^γ receptors - Mast cell activation and vascular perimability - more leukocytes to area 

• Tissue damage

• Non–organ-specific autoimmune diseases

• Examples: SLE, RA, post-streptococcal glomerulonephritis)

Hypersensitivity - Type IV (DTH, 2-3 days)

• Mediated by T cells (Th1, Th17, Tc) – not antibodies

• Activated T cells secrete cytokines and chemokines IFN-γ, TNF → recruit & activate macrophages

• Macrophages release IL-12, TNF → amplify inflammation - Tissue damage from macrophage degranulation & cytotoxic T cells

• Chronic response → granuloma formation (macrophages, giant cells, eosinophils, T cells, fibroblasts)

• Organ-specific autoimmune diseases

• Examples: type 1 diabetes, contact dermatitis, multiple sclerosis; also chronic infections (e.g., TB)

Novel therapeutic approaches

Resolution of Inflammation

Specialized Pro-Resolving Mediators (SPMs)

• Derived from omega-3 fatty acids (resolvins, protectins, maresins)

• Actively resolve inflammation without suppressing immunity - unlike immunosuppressants 

• Reprogram white blood cells

• Reduce neutrophil infiltration, enhance clearance of debris

What happens if Resolution fails?

Therapeutic potential of SPM (Specialized Pro-Resolving Mediators)

• Disruptions in resolution mechanisms, have been observed in most, chronic inflammatory diseases

• SPM-based therapies could restore the immune system’s natural ability to resolve inflammation => prevent or terminate uncontrolled, chronic inflammation

• Therapeutic potential under investigation