Autoimmunity and Immunologically-Mediated Disease

• Innate immune system:

  • Response is non-specific
  • Exposure leads to immediate maximal response
  • Cell-mediated and humoral components
  • No immunological memory
  • Found in nearly all forms of life
• Adaptive immune system:

  • Pathogen and antigen specific response
  • Lag time between exposure and maximal response
  • Cell-mediated and humoral components
  • Exposure leads to immunological memory
  • Found only in jawed vertebrates
• Self-tolerance:

  • A lot of the mechanisms relating to self tolerance relate to the adaptive immune system - so it's important that the immune system recognises its own antigens as self-antigens so that it doesn't attack itself
  • Inherent property that allows response against foreign antigens without attacking self
  • Multiple tolerance mechanisms prevent autoimmunity - checkpoints
  • Mechanisms of tolerance:
  • Central - tolerance induced during development of T cells in thymus
  • Peripheral - control of auto-reactive cells through non-thymus dependent processes
• Tolerance in lymphocyte development can be central or peripheral - central tolerance:

  • In thymus Autoimmune Regulator Event (AIRE) expresses a variety of peripheral tissue antigens
  • While T cells are being developed, they're exposed to these peripheral tissue antigens that they need to tolerate, so they're either inactivated or when they're exposed to the antigen they die and don't develop further...
  • Recognition of self antigen by immature lymphocyte leads to NEGATIVE signal causing death or inactivation
• Tolerance in lymphocyte development can be central or peripheral - peripheral tolerance:

  • Immune Privileged sites - eye/brain/foetal trophoblast - immune system doesn't get to these parts of the body - therefore doesn't start to attack them with T cells or antibodies
  • Anergy - T cell receptor engaged to antigen without concomitant co-stimulation - therefore activation doesn't occur and cell damage doesn't occur
  • Regulation - Regulatory T cells can suppress effector functions of other immune cells and enforce tolerance
• Autoimmunity:

  • Failure of central or peripheral tolerance in lymphocyte development results in activated T cells and antibodies directed against self-antigens
  • This results in tissue damage & altered physiological function
  • Release of more self-antigen too
  • Autoantigens are almost impossible to clear
  • Once initiated, autoimmune disease tends to be active for a very long time
• Incidence of autoimmunity:

  • 2% of population develop an autoimmune disease
  • Women far exceed men in terms of being affected
  • Older adults have more problems with autoimmune diseases
  • Smaller thymus
  • Fewer functional lymphocytes - may be less control over some of the lymphocytes that have autoantigen selection
  • Increased incidence of infection
  • Infection may generate T cells and antibody responses that can cross react with self-antigen
  • Higher levels of autoimmunity
  • Increased T cells for self-antigens
  • Reduced risk of autoimmunity disease itself
  • Related to T regs

  
• Genetic effects on autoimmunity:

  • Affect availability (in the system) and clearance (from the system) of autoantigen
  • Apoptosis
  • Signalling thresholds
  • Expression of co-stimulatory molecules
  • Antigen presentation - HLA type
• Autoimmunity - genetics and environment:

  • Specific causes of most autoimmune diseases are unknown
  • Genetic risk factors have been identified (e.g. Certain MHC class II molecules and other genes), but many predisposed individuals will never get the disease
  • Epidemiological studies of genetically identical animals show strong role of environmental factors in the initiation of autoimmunity: toxins, drugs, viral & bacterial infections
• Autoimmune diseases can be classified by nature of immune response (antibody-mediated or T-cell mediated). But this is an imprecise way of doing it; the immune system is interlinked and antibody generation will also rely on the generation of T cells.
• Classification of autoimmune diseases is difficult:

  • Organ specific examples:
  • Type 1 diabetes mellitus
  • Goodpasture's syndrome
  • Multiple sclerosis
  • Crohn's disease
  • Psoriasis
  • Vitiligo
  • Systemic examples:
  • Rheumatoid arthritis
  • Scleroderma
  • Systemic lupus erythematosus
  • Polymyositis
  • Primary Sjogren's syndrome

  Not all autoimmune diseases can be classified this way - autoimmune haemolytic anaemia (can occur in isolation or in association with SLE)
• In autoimmunity, multiple components of the immune system are typically recruited, but the significance of each varies by disease - eg:

  • Myasthenia Gravis: autoantibodies against acetylcholine receptor play a main role in causing disease symptoms (immune complex deposits, complement activation & FcR = inflammation)
  • Type 1 diabetes mellitus, IBD, psoriasis: effector T cells are the main destructive agents (directly & macrophages)

  However, as in the response to pathogens, ALL aspects of the immune system have a role.
• Autoimmune diseases involve all aspects of the immune response:

  • Disease: Systemic Lupus Erythematosus
  • T cells: Pathogenic help for antibody
  • B cells: Present antigen to T cells
  • Antibody: Pathogenic
• Autoimmune diseases involve all aspects of the immune response:

  • Disease: Type I diabetes
  • T cells: Pathogenic
  • B cells: Present antigen to T cells
  • Antibody: Present, but role unclear
• Autoimmune diseases involve all aspects of the immune response:

  • Disease: Myasthenia Gravis
  • T cells: Help for antibody
  • B cells: Antibody secretion
  • Antibody: Pathogenic
• Autoimmune diseases involve all aspects of the immune response:

  • Disease: Multiple Sclerosis
  • T cells: Pathogenic
  • B cells: Present antigen to T cells
  • Antibody: Present, but role unclear
• Organ specific autoimmune disease - endocrine:

  • Results from autoimmune processes because there may be 1 or several effects on the gland:
  • Destruction
  • Cellular infiltration
  • Uncontrolled stimulation
  • Blockade of stimulation
• Organ specific autoimmune disease - endocrine:

  • Addison's disease
  • Adrenal insufficiency
  • Symptoms result from a lack of cortisol
  • Fatigue, depression
  • Addisonian crisis
  • Collapse
  • Abdominal pain
  • Hypotension
  • Increased pigmentation of skin folds, buccal mucosa and scars
• Organ specific autoimmune disease - endocrine:

  • Diabetes mellitus - Type 1
  • Immunological destruction of pancreatic islets of Langerhans
  • Defective insulin production - results in hyperglycaemia
  • Care with hypoglycaemia resulting from missed meal
  • Candida/dry mouth/sialosis, glossitis
  • Severe periodontitis may upset glycaemic control
  • Vigorous treatment of oral and facial infections
• Organ specific autoimmune disease - endocrine:

  • Thyroid disease
  • Hypothyroidism
  • Weight gain, hypothermia, lassitude (fatigue), dry skin, cardiac failure, ischaemic heart disease, anaemia
  • Analgesics and sedatives including general anaesthetics can precipitate myxoedema coma
  • Most commonly affected endocrine gland
  • Hyperthyroidism
  • Weight loss, anorexia, diarrhoea, anxiety, tremor, sweating, exophthalmos (bulging eyes)
  • If undiagnosed can be at anaesthetic risk
  • Carbimazole can cause agranulocytosis which can cause oral or oropharyngeal ulceration
• Organ specific autoimmune disease - non-endocrine:

  • Coeliac disease
  • Gluten sensitive enteropathy
  • Strong genetic influence
  • Gluten activates a series of immunological mechanisms leading to small intestinal damage
  • Loss of villi
  • Crypt hyperplasia
  • Chronic inflammatory infiltrate
• Organ specific autoimmune disease - non-endocrine:

  • Coeliac disease - clinical features:
  • Cachexia (weight loss), oedema, vitamin deficiency and anaemia
  • Mostly present <5 years or 30-40
  • Poor energy
  • Failure to thrive
  • Diarrhoea/constipation
  • Anaemia (iron or folate)
  • Aphthous ulcers (mouth ulcers)
  • Dermatitis herpetiformis
• Organ specific autoimmune disease - non-endocrine:

  • Coeliac disease - investigation:
  • Anti-endomysial antibody positive
  • Anti-TTG antibody positive
  • Biopsy
  • Coeliac disease - management:
  • Strict gluten-free diet (barley, wheat and rye)
• Organ specific autoimmune disease - non-endocrine:

  • Haematological disease
  • Autoimmune haemolytic anaemia
  • Acute severe or mild chronic anaemia
  • Associated with thrombocytopenia
  • Autoimmune neutropenia (low number of neutrophils)
  • Oral ulceration
  • Increased risk of infection
  • Prophylaxis with antibacterials and anti-fungals
  • Immune thrombocytopenia purpura
  • Idiopathic or preceded by viral infection
  • Purpura, bruising and nose bleeds
  • May need high dose steroids, splenectomy or rituximab
• Organ specific autoimmune disease - non-endocrine:

  • Skin conditions - bullous pemphigoid
  • Elderly
  • Subepidermal blisters
  • Mucous membranes
  • Oral prednisolone or azathioprine
• Organ specific autoimmune disease - non-endocrine:

  • Skin conditions - pemphigus vulgaris
  • Rare blistering disorder
  • Non-healing erosions of mucous membranes
  • Flaccid blisters on skin
  • High dose steroids
• Organ specific autoimmune disease - non-endocrine:

  • Kidney disease (can be autoimmune or can progress to chronic renal failure)
  • Can be autoimmune
  • Non-organ specific - Wegeners granulomatosis, microscopic polyarteritis, SLE and Goodpastures
  • Goodpastures
  • Anti-GBM antibodies bind to both glomerular and alveolar basement membrane
  • Type II hypersensitivity
• Organ specific autoimmune disease - non-endocrine:

  • Kidney disease (can be autoimmune or can progress to chronic renal failure)
  • Can progress to chronic renal failure
  • Bleeding tendencies
  • Impaired drug excretion
  • Steroid treatment
  • Hypertension
  • Infections increase
  • Anaemia
  • Dysrhythmias
• Organ specific autoimmune disease - non-endocrine:

  • Liver specific conditions
  • Autoimmune hepatitis
  • Primary biliary cirrhosis
  • Nervous system specific conditions
  • Guillain-Barre
  • CIDP (chronic inflammatory demyelinating polyradiculoneuropathy)
  • Myasthenia gravis
• Organ specific autoimmune disease - non-endocrine:

  • Non-organ specific
  • Multi-system
  • Non-specific features
  • Fatigue, arthralgia (aches and pains), myalgia (muscles aching), xerostomia, rash, GERD, anaemia, SOB, enlarged lymph nodes, salivary gland enlargement
• Organ specific autoimmune disease - non-endocrine:

  • Rheumatoid arthritis
  • A common painful inflammatory arthritis
  • Leads to progressive joint destruction
  • Associated with extra-articular disease, Sjogren's syndrome
  • Diagnosis is clinical
  • ESR (erythrocyte sedimentation rate) and CRP (C reactive protein) will be raised
  • Rheumatoid factor, IgG anti-IgG, anti-CCP autoantibody found in 65%
• Organ specific autoimmune disease - non-endocrine:

  • Rheumatoid arthritis - extra-articular manifestations
  • Nodules
  • Synovitis
  • Muscle wasting
  • Cardiac involvement
  • Nervous system
  • Vasculitis
  • Eye involvement
  • Scleritis
  • Uveitis
  • Gastrointestinal problems
  • Felty's syndrome
  • Splenomegaly & neutropenia
  • Sjogren's syndrome
• Connective tissue diseases:

  • Systeimc lupus erythematosus - clinical features
  • Arthritis
  • Pleurisy, pericarditis
  • Glomerulonephritis
  • Anaemia, thrombocytopenia
  • Neurological disease
  • Cardiac disease
  • Cutaneous features: oral ulceration, photosensitive rashes, raynauds
• Connective tissue diseases:

  • Systeimc lupus erythematosus - investigations (diagnostic tests)
  • Antinuclear antibodies
  • Antibodies to double-stranded DNA
  • Low complement (consumption of C4, C3)
  • Raised IgG levels
  • Raised ESR (inflammation)
• Connective tissue diseases:

  • Systeimc lupus erythematosus - dental aspects
  • Anaemia
  • Bleeding tendencies
  • Predisposition to thrombosis
  • Cardiac disease
  • Renal disease
  • Steroid therapy
  • Drug reactions - tetracyclines
• Connective tissue diseases:

  • Scleroderma
  • Multisystem disorder
  • Skin changes
  • Oedema
  • Fibrosis and contraction
  • Atrophy
• Connective tissue diseases:

  • Scleroderma - 3 main presentations:
  • Morphoea
  • Limited systemic sclerosis
  • Diffuse systemic sclerosis
  • Very evident changes of skin affecting face and mouth
  • Hands may develop flexion deformities
  • Intracutaneous and subcutaneous calcification
  • Renal involvement
  • Anti-Scl70 antibodies
• Connective tissue diseases:

  • Scleroderma - limited (CREST):
  • Calcinosis
  • Raynauds (fingers become white)
  • Oesophageal immotility (difficulty swallowing)
  • Sclerodactyl (sausage-like fingers)
  • Telangiectasia
• Connective tissue diseases:

  • Scleroderma
  • Pulmonary hypertension
  • Anti-centromere antibodies
  • Periarticular involvement of temporomandibular joint with microstomia
  • Constriction of oral orifice
  • Thickened, stiffened tongue
  • Oral telangiectasia
  • Widening of periodontal membrane space without tooth mobility
  • Potential problems for general anaesthetic
  • Dysphagia
  • Pulmonary, cardiac, and renal disease
• Connective tissue diseases:

  • Sjogren's syndrome = triad of dry eyes, dry mouth, associated inflammatory arthritis
  • Lymphocytic infiltrate of lacrimal and salivary glands
  • Also affects other exocrine glands in pancreas, lungs and vagina