Immunology - Management Issues For Dentists

• The role of the immune system is to protect from infection.
• What can go wrong with the immune system:

  • Immunodeficiency - if all components of the immune system aren't working correctly then you'll get an excessive infection (immunodeficiency)
  • Allergy
  • Autoimmunity
• With the immune system - there's a balance between:

  • Recognising and eliminating pathogens
  • Destroying virally infected cells
  • Destroying tumour cells

  And

  • Tolerating commensal organisms
  • Tolerating healthy self antigens

  One side = fighting infections, other side = tolerating our own antigens

  
• Often we see immunodeficiency, allergy and autoimmunity all occurring in the same patient. But we want the immune system to tolerate commensal organisms and healthy self-antigens.
• In immunodeficiency, the balance tips in favour of tolerating commensal organisms and tolerating healthy self antigens. The ability to recognise and eliminate pathogens, destroy viral infection cells, and destroy tumour cells is reduced.
• In autoimmunity/allergy, the balance tips towards recognising and eliminating pathogens, destroying viral infection pathogens, and destroying tumour cells. The ability to tolerate commensal organisms and tolerate healthy self-antigens is reduced.
• Sometimes both branches of the immune system can be broken.

  
• Parts of the immune system:

  • Innate
  • A basic immune system - nothing changes within it - it's fixed - it's the same - no matter which pathogen it comes across
  • Constant level of protection
  • 1st level of defence
  • Adaptive
  • Specific protection
  • Long-lasting memory
  • When immunised, we're stimulating to adaptive immune system to produce long-term memory to protect against future infection
• Innate immune system:

  • Barriers
  • Skin
  • Endothelium
  • Soluble (humoral) mechanisms
  • Enzymes (lysozyme) in saliva
  • Low pH in stomach
  • Complement system
  • Cells
  • Phagocytes - link with adaptive immune system (activate lymphocytes)
  • Complement
• Once the barriers in the innate immune system are broken, soluble mechanisms are used to stop the infection. Soluble mechanisms will breakdown or inactivate many organisms.
• Cells are needed to activate the immune system once an organism has got into the body. Phagocytes are the main part of the innate immune system in terms of cells because they recognise constant molecules on the surface of pathogens - allows them to consume them and then break them down and then present them to the adaptive part of the immune system.
• Some of the by-products of the complement pathway will attract other cells into the immune system and to the area of inflammation. Attracts phagocytes, T cells and B cells.

  
• Complement - part of the soluble mechanisms:

  • Activation
  • Classical
  • Alternate
  • MBL (mannose binding lectin)
  • Results in activation of final lytic - complement system forms a series of enzymes which can link up to form a terminal lytic compound, which inserts itself into the surface of pathogens - causes lysis of the pathogens - therefore can be v effective

  
• Adaptive immune system - organs of the immune system:

  • Lymphoid organs
  • Central (primary) lymphoid organs (where lymphocytes are produced)
  • Bone marrow (where B cells are predominantly produced)
  • Thymus (where T cells find their place)
  • Secondary lymphoid organs (where adaptive responses start)
  • Adenoids, tonsils, lymph nodes, spleen, Peyers patch, appendix
  • Mucosa

  
• Immunodeficiency occurs when one or more components of the immune system is defective.

  • Acquired/secondary
  • This is what is seen in the majority of cases
  • Inherited/primary
  • Rare in comparison to acquired/secondary immunodeficiency
• Consequences of immunodeficiency:

  • Excess of infection
  • Increased autoimmune disease
  • Increase in malignancy
• Adaptive immune system:

  • Soluble (humoral) mechanisms
  • Antibody (immunoglobulins) - if produced appropriately is very specific to the organ that you've been infected with - initially IgN will be produced, but then they'll switch once they've honed in on which pathogen they need to be fighting to produce IgG
  • When vaccinated, the production of IgG will be a lot quicker and therefore the fight will be much more effective from an earlier stage
  • Protein which recognise 'antigens' on pathogens - and other things

  DCs = dendritic cells

  
• Symptoms of immunodeficiency (SPUR):

  • Serious infections (in and out of hospital from an early age)
  • Persistence of infections (difficult to clear them)
  • Chronic GI viruses, oral candidiasis
  • Unusual sites
  • Liver abscess
  • Or unusual organisms
  • Pneumocystis
  • Aspergillus
  • Recurrent infections
• Signs of immunodeficiency:

  • Acute infection
  • Chronic infection - eg candidiasis
  • Damage from infections - eg bronchiectasis
  • Autoimmune features
  • Endocrine disease
  • Skin problems - eg vitiligo
  • Specific findings - eg eczema, thrombocytopenia (low platelet counts), congenital heart disease
• Warning signs of immunodeficiency:

  • 8 or more new ear infections in 1 year
  • 2 or more serious sinus infections in 1 year
  • 2 or more pneumonias in 1 year
  • Recurrent, deep skin or organ abscesses
  • 2 or more deep-seated infections, such as osteomyelitis, cellulitis, or sepsis
• Warning signs of immunodeficiency:

  • Antibiotics for 2 months without effect
  • Surgical intervention for chronic infection eg lobectomy, recurrent incision of boils
  • Persistent thrush in mouth or elsewhere on the skin after age 1 year
  • Failure to thrive
  • Family history of immunodeficiency
• Classification of immunodeficiency:

  • Primary
  • Antibody/B cells
  • T cells
  • Combined B and T cell
  • Neutrophils
  • Complement (classical pathway)
  • Complement (terminal and alternate pathways)
  • Innate
  • Secondary
• If you have a B cell defect (immunodeficiency) you're more likely to get bacterial infections:

  • Typically from capsulated organisms (present with recurrent sinus or chest infections, sometimes skin infections, and can get meningitis, and often tonsillitis too)
  • Streptococci
  • Haemophilus
  • Meningococci
  • Staphylococci
  • Campylobacter

  You're also more likely to get protozoal infections and abscesses, but fungi and virus problems are uncommon unless there's involvement with T cells too.
• If you have a T cell defect (immunodeficiency) you're more likely to get:

  • Problems with fungi
  • Pneumocystis
  • Pneumonia
  • Cryptococcus
  • Meningitis
  • Toxoplasma
  • Eye, brain
  • Candida
  • GI tract, eye
  • Problems with viral infections - can become out of control
  • Rota virus
  • Polio virus
  • CMV
  • EBV
  • Herpes viruses
  • JC & BK viruses
  • Bacterial infection uncommon
  • No abscesses
• Because T cells are so integral to the function of B cells, you often see T and B cell defects combined.
• If you get immunodeficiency with phagocytic cells:

  • Abscesses - without much inflammation around them
  • Problems with bacterial infection
  • Staphylococci
  • Pseudomonas
  • Problems with fungal infections
  • Aspergillus
  • Nocardia
  • Viral infections uncommon
• If you get immunodeficiency with complement (classical pathway):

  • Problems with bacterial infection
  • Streptococci
  • Meningococci (will present with recurrent meningitis)
  • Viral and fungal infections are rare

  If you get immunodeficiency with complement (alternate and terminal pathways):

  • Neisserial infection
  • Meningitis
• Clinical examples of immunodeficiency:

  • SCID (severe combined immunodeficiency)
  • X-linked agammaglobulinaemia (reduction in or abscence of B cells)
  • Common variable immunodeficiency
  • Chronic granulomatous disease
  • Chronic mucocutaneous candidiasis
  • DiGeorge Syndrome
• SCID (severe combined immunodeficiency) - causes & effects:

  • Multiple genes identified
  • Affected usually from birth
  • T cells absent
  • B cells may be absent
  • Risk of infection is significant
  • Present with viral, fungal and bacterial infections
  • Once they encounter infection it's v hard to clear it
• X-linked agammaglobulinemia (reduction in or absence of B cells) - causes and effects:

  • Presents in boys but girls can be carriers
  • Mutations in btk gene
  • Caused by a problem with the tyrosine kinase involved in B cell maturation
  • Low/absent B cells and reduced immunoglobulins
  • Absent tonsils and other lymph nodes
  • Recurrent bacterial infections
• Common variable immunodeficiency - causes and effects:

  • Multiple gene defects
  • Low but not absent immunoglobulins/antibody
  • Present with recurrent bacterial infections (sinus, lungs, ears, eyes)
  • Autoimmunity (thyroid, alopecia, vitiligo)
  • High risk of malignancy (particularly lymphoma)
• Chronic granulomatous disease - causes and effects:

  • Genetic defects affecting neutrophil oxidative burst (don't produce it - therefore can't kill organisms)
  • Recurrent abscesses
  • Deep-seated
  • Liver, soft tissues
  • Fungal
  • Gingivitis and tooth loss
• Chronic mucocutaneous candidiasis - causes and effects:

  • Genetic defects (AIRE gene)
  • Cytokine abnormalities
  • Failure to clear candidia
  • Endocrine abnormalities (thyroid, parathyroid, adrenal)
  • Nails effected
  • Common problem
• DiGeorge syndrome - causes and effects:

  • Gene deletion on 22q11
  • Thymus doesn't develop - no/reduced T cells
  • Viral, fungal and bacterial infections
  • Cardiac abnormalities
  • Variable learning difficulties
  • Speech difficulties
• Secondary immunodeficiency:

  • Malnutrition - biggest worldwide cause of immunodeficiency
  • Medication
  • Infection - everyone has slight immunodeficiency after an infection
  • Radiotherapy - can take longer to recover from immunodeficiency (can last years rather than weeks or months)
  • Splenectomy (spleen = major source of cells for immune system, so removing that can put you at risk of overwhelming sepsis from encapsulated organisms)
• Secondary immunodeficiency:

  • Drugs
  • Cytotoxics
  • T & B cells, neutrophils
  • Anti-convulsants
  • B cells, neutrophils
  • Carbamizole
  • Neutrophils (mouth ulcers)
  • Immunosuppressive drugs
  • Cyclophosphamide
  • Azathioprine
  • Methotrexate
  • Cyclosporin & tacrolimus
  • Prednisolone > 20mg/day
  • Monoclonal antibodies
  • Rituximab (anti-CD20), anti-TNFs
• Dental implications of immunodeficiency:

  • History
  • Check for recurrent infections; family history [genetic]; check for drugs
  • Examination
  • Candidiasis, oral hairy leukoplakia, severe gingivitis, tooth loss, mouth ulceration, dry mouth, tonsils
  • Skin changes [vitiligo, alopecia, telangiectasia]
• Causes of oral candida:

  • Antibiotic therapy
  • Steroid inhalers
  • Dentures
  • Secondary immunodeficiency eg HIV, drugs
  • Connective tissue disease
  • Sjogren's syndrome
  • Primary immunodeficiency eg CMC (chronic mucocutaneous candidiasis)
  • Xerostomic effects of medications
  • Dietary
  • Endocrine
  • Miscellaneous - alcohol, caffeine, chronic Hep C, smoking
• Causes of mouth ulcers:

  • Aphthous
  • Nutritional deficiencies
  • Behcet's syndrome
  • SLE (systemic lupus erythematosis)
  • Cancer
  • Crohn's disease
  • Infection - viral (HSV), (bacterial)
  • Trauma
  • Haematological malignancy
  • Medications eg methotrexate
  • Oral dermatoses - lichen planus, pemphigoid, pemphigus
• Causes of gingivitis & tooth loss:

  • Pregnancy
  • Cyclosporin
  • Scurvy
  • Anticonvulsants
  • Chronic granulomatous disease (primary immunodeficiency)
  • Poor oral hygiene