Specific Ocular Immunity Immune Dysfunction Session 6 PDF

2024/06/02 CONTENT...

2024/06/02 CONTENT PART 1: Specific ocular immunity & ocular infections SPECIFIC Dr Leriska Haupt OCULAR PART 2: Haematologist IMMUNITY Immune dysfunction: Hypersensitivity Dept of Haematology and Cell Biology IMMUNE DYSFUNCTION PART 3: Immune dysfunction: Immunodeficiency T: 051 401 9111 [email protected] www.ufs.ac.za T: 051 401 9111 [email protected] www.ufs.ac.za Conjunctival immune Uveal tract response Acquired Tears immune PART 1: response SPECIFIC OCULAR IMMUNITY OCULAR INFECTIONS Ocular Physical Other barriers defence measures mechanisms 1  2024/06/02 PHYSICAL BARRIERS / NATURAL STRUCTURES TEARS The orbital skeletal structure minimises potential trauma. Prevent drying of the cornea The eyelid architecture is relatively impermeable to large Flush foreign particles from the ocular surface molecules. Transport antimicrobial proteins The eyelid blink reflex and ciliary movements rapidly – Lactoferrin, lysozyme, lipocalin, and beta-lysin clear foreign objects from the ocular surface. Transport immunoglobulins to the ocular surface to Conjunctival populations of non-pathogenic bacteria prevent infections prevent attachment and colonization of invasive bacteria. – Mostly IgA The tear flow and reflex tearing remove microorganisms Bind bacteria and prevent adherence to epithelium and cellular debris Neutralise bacteria and viruses – Drainage into the nasolacrimal duct Graefe's Archive for Clinical and Experimental Ophthalmology; Chapter 14; 961-990 CONJUNCTIVAL IMMUNE RESPONSE UVEAL TRACT Continuous layer of iris, ciliary body and choroid Thin, transparent, vascular mucous membrane – Covers the cornea Main area for lymphocytes, lymphatic drainage – Includes sensitised lymphocytes Major source of immune components in the cornea – Contains antibodies – Produce IgA – Contains macrophages, neutrophils, mast cells, lymphocytes Vascular structure – Contain lymphoid tissue (MALT) – “Filters blood” for antigens etc. Show features of inflammation/allergic reaction – Redness due to dilated vessels – Chemosis (“swelling”) 2  2024/06/02 ACQUIRED IMMUNE RESPONSES OTHER PROTECTIVE MEASURES Dendritic cells in the cornea: Keratocytes Secrete defensins – Antigen-presenting cells – Antimicrobial activity against bacteria, fungi and viruses – Accelerate epithelial healing – Lead to cell-mediated immune response Corneal nerves Reflexive movements to protect the eye Conjunctiva-Associated Lymphoid Tissue (CALT): Sensations of discomfort and pain – Contain CD4+ and CD8+ T-cells, B-cells and abundant IgA immunoglobulins Complement Concentrated in the peripheral cornea – Activation of complement by either the classical or alternate pathway Scleral immunology Dense fibrotic tissue Acid mucopolysaccharides OCULAR INFECTIONS INTRODUCTION Eye infections may be classified according to: – the infectious organism involved, or – the structure within the eye that is affected. Wide variety of bacteria, viruses, fungi, and parasites Different structures that can become infected are determined by the anatomy of the eye OCULAR INFECTIONS Severity ranges from generally self-limiting conditions to those that threaten sight. 3  2024/06/02 Adnexal Anterior uveitis Eyelid = pre-septal cellulitis Red eye Orbital tissue = orbital cellulitis Uveitis Deep aching pain/ Lachrymal gland = dacryoadenitis photophobia Lachrymal drainage system = dacryocystitis Endophthalmitis Blurred vision Periorbital tissues = cellulitis Signs Severe cases: Red eyes hypopyon Discharge Conjunctivitis +- Pain/photophobia Signs: Acute red eye & Severe pain Posterior uveitis Progressively worsening vision Floaters and visual Hypopyon may be present changes Raised intraocular pressure NO redness or History: significant pain Kerato- Eye surgery Retinal involvement: conjuctivitis Penetrating ocular trauma Blind spots/ Immunosuppression flashing lights May have systemic features: Signs Fever Red eye Joint pain Pai n/photophobia +++ Sepsis Ulceration EMERGENCY! Los s of vision Episcleritis See Hyp opyon if severe & autoimmunity Keratitis *Immune response leads to worse Scleritits consequences than infectious agent INFECTIOUS AGENTS INFECTIOUS AGENTS BACTERIA BACTERIA May cause severe Staphylococcus spp. Pseudomonas aeruginosa disease! – S. aureus & coagulase-negative Staphylococcus – Causes very rapid ulceration Streptococcus pneumoniae Serratia marcescens Haemophilus influenzae Chlamydia trachomatis Neisseria gonorrhoeae – Infection both in neonates and in sexually active adults – Infection both in neonates and in sexually active adults – Responsible for trachoma – Leads to scarring and loss of vision after repeated infections Other: Staphylococcal infection – Mycobacterium spp. Pseudomonas aeruginosa Chlamydia eye infection in the newborn – Moraxella spp. – Klebsiella spp. – Nocardia spp. 4  2024/06/02 INFECTIOUS AGENTS VIRUSSES May cause Varicella zoster virus Herpes simplex virus severe disease! Herpes simplex virus – Most commonly associated with serious corneal disease Varicella zoster virus – Immunocompromised patients at high risk – Herpes zoster ophthalmicus (HZO) – Conjunctivitis, keratitis, episcleritis, scleritis, uveitis, optic neuritis, retinitis, ocular motor palsies and neurotrophic keratopathy – Complications may develop months or years after the acute phase – If not diagnosed and treated adequately = may lead to permanent damage Rubella virus – May infect lens and lead to blindness Keratitis INFECTIOUS AGENTS VIRUSSES INFECTIOUS AGENTS PROTOZOA Adenovirus – Certain strains (notably types 8, 19 and 37) cause epidemic Acanthamoeba keratoconjunctivitis – Acanthamoeba is a microscopic, Enteroviruses free-living protozoa – Including coxsackie virus – Relatively common in the environment (water/air) Cytomegalovirus – Patients suffering from AIDS Acanthamoeba keratitis: Avian paramyxovirus serotype 1 – Uncommon but serious condition – Newcastle disease – May progress to severe visual loss – Spread from poultry – Present with severe pain, disproportionate to the signs. Other – May develop after corneal trauma, often minor in nature – Mumps virus Contact lenses: – Epstein-Barr virus – 93% of cases arise in association with contact lens wear – Associated with daily wear or extended wear contact lenses 5  2024/06/02 INFECTIOUS AGENTS INFECTIOUS AGENTS PROTOZOA FUNGI Toxoplasma gondii Fusarium spp. – Transmitted from cats Aspergillus spp. – Ocular toxoplasma Candida spp. – Unilateral or bilateral – Predominantly involves acute chorioretinitis – Severe inflammation and necrosis – May be recurrent and lead permanent damage / blindness – Can be transmitted from mother to child WHAT IS HYPERSENSITIVITY? Also called “hypersensitivity reaction” or “intolerance”. A set of undesirable, abnormal reactions produced by the normal immune system – Reaction against harmless "environmental" agents PART 2: – Adaptive immune system IMMUNE DYSFUNCTION: HYPERSENSITIVITY Includes allergies and autoimmunity May be damaging, uncomfortable or occasionally fatal. 6  2024/06/02 WHAT IS AN ALLERGEN? CHARACTERISTICS OF ALLERGENS An antigen that induces hypersensitivity – Allergic reaction: when the immune system overreacts to a Usually proteins +/- carbohydrates harmless substance known as an allergen Low dose Can be almost any substance Low molecular weight Usually the substance is not intrinsically harmful Highly soluble Stable Common allergens include: – Pollen Able to bind host MHC class II – Grass – Dust – Medication – Food SENSITISATION HYPERSENSITIVITY REACTIONS First exposure to allergen Become sensitised = produce IgE antibodies Atopic individuals – Multiple types of allergic reactions to multiple allergens – Usually starts in childhood Non-atopic individuals – Usually only sensitised to one specific antigen – Can start any age Not all exposures to allergens lead to sensitisation AND Not all sensitisation events lead to an allergic reaction 7  2024/06/02 STAGES OF TYPE I First exposure to antigen/allergen TYPE I (IMMEDIATE-TYPE) HYPERSENSITIVITY HYPERSENSITIVITY Production of IgE SENSITISATION PHASE IgE fixed on mast cells Antigens (allergens) induce the formation of IgE antibodies. Subsequent exposure to antigen/allergen IgE on mast cells are cross-linked Leads to degranulation of mast cells Degranulation of mast cells: and basophils and later to activation - Release mediators: histamine, heparin, etc. of eosinophils. -Recruitment of basophils = release of more EFFECTOR PHASE mediators Physiologically occur in parasitic infections. Recruitment of eosinophils from bone marrow LATE PHASE RESPONSE Deterioration of symptoms hours later EFFECTS OF HISTAMINE Constriction of smooth muscles – Bronchiole constriction → wheezing – Constriction of intestine → cramps, diarrhoea Vasodilation – Increased fluid into tissues Immune cells release histamine – Swelling or fluid in mucosa when an allergen is encountered Activates enzymes – Tissue breakdown 8  2024/06/02 ANAPHYLAXIS WHAT IS ATOPY? Allergen directly absorbed into blood A genetic predisposition to develop immediate hypersensitivity reactions stream of a sensitised individual. against common environmental antigens. Connective tissue mast cells associated Produce IgE responses against non-parasitic antigens with bloodstream immediately activated. – Normally these antigens do not lead to a antibody response or lead to a response of a different isotype (e.g. IgG) Widespread release of histamine. – Atopic individuals have higher levels of IgE and eosinophils. Leads to generalised anaphylaxis or local tissue reactions. Vasodilatation and increased permeability of blood vessels. Manifested as: Increased fluid in tissue with fall in blood – Allergic conjunctivitis pressure. – Allergic rhinitis (hay fever) – Asthma Symptoms vary – Atopic dermatitis (eczema) Mild = urticaria (large, itchy red swellings all over body) – Food allergy Severe = anaphylactic shock (may be fatal) TYPE I HYPERSENSITIVITY & THE EYE TYPE I HYPERSENSITIVITY & THE EYE ALLERGIC CONJUNCTIVITIS ALLERGIC CONJUNCTIVITIS – CLINICAL PICTURE Most common allergic response of the eye Symptoms Signs Itching Oedema History: – May be bilateral – Conjunctiva / eyelid – Seasonal/Perennial Tearing Prominent blood vessels Perennial: ? atopic patient Foreign body sensation Atopic patients – Family history Redness – May show dry, scaly eyelid skin Photophobia – Long standing allergy may lead – Other allergic reactions to permanent changes E.g. asthma, rhinitis Pain – History of itching Without itching, the diagnosis of allergic conjunctivitis is unlikely! 9  2024/06/02 PATHOPHYSIOLOGY TYPE I HYPERSENSITIVITY & THE EYE ALLERGIC CONJUNCTIVITIS ALLERGIC CONJUNCTIVITIS Differential diagnosis: Management: Bacterial conjunctivitis Avoid allergen Viral conjunctivitis Topical treatment (antihistamines) Mast cell stabilisers Corticosteroids TYPE II (ANTIBODY-MEDIATED) HYPERSENSITIVITY ANTIBODY DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC) Specific antibodies bind to cell surface antigens – IgM and/or IgG antibodies Complement activation, ADCC and phagocytosis Physiological functions: – Elimination of unwanted organisms (bacteria/viruses etc.) – Removal of potential malignant cells 10  2024/06/02 TYPE II (ANTIBODY-MEDIATED) HYPERSENSITIVITY TYPE II HYPERSENSITIVITY & THE EYE CLINICAL EXAMPLES MYASTHENIA GRAVIS Autoimmune haemolytic anaemia Weakness and rapid fatigue of muscles under voluntary control. – Antibody directed against an antigen on the red cell surface – Destruction of red cell in spleen by macrophages Antibodies against receptors of the nerves: – Leads to "fatigue" of the nerve and paralysis of the muscle after a time. Incompatible transfusion Presents with ptosis of the eyelids. – Antibodies formed against foreign red cells – Destroyed intravascular by complement Management: – Immunosuppression TYPE III (IMMUNE-COMPLEX MEDIATED) TYPE III (IMMUNE-COMPLEX MEDIATED) HYPERSENSITIVITY HYPERSENSITIVITY Rapid influx of antigen overwhelms coping mechanisms Antibody reacts to a soluble antigen Deposition of immune complexes on vessel walls/tissue – Forms a network of Leads to damage by complement or neutrophils antigen:antibody complexes Local or systemic effects: – Local: farmers lung (inhalation of mould spores) Physiological function: – Systemic: certain autoimmune diseases (e.g. SLE) – Remove bacterial endotoxin – Normally broken apart by complement and removed by macrophages in the spleen 11  2024/06/02 TYPE III HYPERSENSITIVITY & THE EYE STEVENS-JOHNSON SYNDROME Also known as toxic epidermal necrolysis Rare, serious reaction – Caused by drugs, infections, etc. – HLA association Involves skin and mucous membranes – Presents with flu-like symptoms and painful rash – May involve the eye Management – Symptomatically Long term complications – Serious eye problems – Can lead to blindness TYPE IV (DELAYED TYPE) HYPERSENSITIVITY Also called: cell-mediated immune memory response Contact with antigen leads to CD4+ T-helper cell activation Delayed reaction: 1 - 2 weeks Subsequent exposure – T-helper cells secrete cytokines Recruit macrophages/ eosinophils/ cytotoxic T-cells – 48-72 h post-exposure 12  2024/06/02 TYPE IV OR DELAYED TYPE HYPERSENSITIVITY TYPE IV HYPERSENSITIVITY &THE EYE CORNEAL ALLOGRAFT REJECTION Host immune response against the antigens in the donor Physiological function corneal button – Clearance of intracellular pathogens Tissue destruction brought about by cells and mediators Persistence of pathogen leads to damage of normal tissue Direct pathway by macrophages/products – Recognition of non-self MHC class I molecules Indirect pathway – Presentation of donor antigen by host APC to naive CD4+ T-cells Examples: – Skin reaction to nickel – Tuberculosis infection – Tuberculin test PART 3: IMMUNE DYSFUNCTION: IMMUNODEFICIENCY 13  2024/06/02 IMMUNODEFICIENCY IMMUNODEFICIENCY DEFINITION MECHANISMS An innate, acquired, or induced inability to develop a normal Loss or reduction of: immune response. Cell type Cell numbers Predisposing one to infection, certain chronic diseases and cancer. Cell function – Receptors Primary: immune deficiency is the cause of disease. – Cell signaling – Usually genetic (hereditary) – Cytokine production – Ig production Secondary: immune deficiency is the result of disease (e.g. HIV – Co stimulation impairment infection) or other external factors (e.g. chemotherapy). – Intracellular killing – Acquired – Extravasation impairment IMMUNODEFICIENCY PRIMARY IMMUNODEFICIENCY CLINICAL FEATURES B-cells T-cells Combined B- Phagocytic Complement & T-cell cell deficiency Increased susceptibility to infection: (Humoral (Cellular deficiency deficiency immunity) immunity) – Recurrent infections – Resistant infections – Infection with low virulence pathogens IgA DiGeorge SCID Neutrophil Alternative/ Increased incidence of malignancy (esp. lymphoma) deficiency numbers / Classical/ function Common Bruton’s pathway 14  2024/06/02 PRIMARY IMMUNODEFICIENCY Over 50 separate genetic defects in lymphocytes or monocytes/macrophages are now known Mostly very rare Mostly present in infants and young children However: majority of patients with primary immunodeficiency do not yet have a defined condition T: 051 401 9111 [email protected] www.ufs.ac.za – ‘Classified’ as having ‘common variable immunodeficiency – CVID’ PRIMARY IMMUNE DEFICIENCY DISORDERS PRIMARY IMMUNE DEFICIENCY DISORDERS HUMORAL IMMUNITY (B-CELLS/ANTIBODIES) HUMORAL IMMUNITY (B-CELLS/ANTIBODIES) a. Selective IgA-deficiency b. X-linked (Bruton’s) Hypo- or Agammaglobulinaemia Decreased/total lack of serum IgA X-linked, only occurs in male infants Relatively common (1 in 800) First 5-6 months - protection by maternal IgG Failure in terminal differentiation of B cells Recurrent bacterial diseases starting at end of first year of Most people healthy, some show increased susceptibility life to respiratory, alimentary and urogenital tract infections Defective B-cell receptor: Treatment with immunoglobulin and standard blood – B-cell signal transduction affected product transfusions are contraindicated: anaphylactic – Inability to form mature B-cells reactions – Low levels of IgG – Require IgA deficient plasma, washed red cells and platelets for Short life span transfusions 15  2024/06/02 PRIMARY IMMUNE DEFICIENCY DISORDERS PRIMARY IMMUNE DEFICIENCY DISORDERS HUMORAL IMMUNITY (B-CELLS/ANTIBODIES) CELLULAR IMMUNITY (T-CELLS) c. Other a. Congenital thymus aplasia (DiGeorge syndrome) Hyper-IgM syndrome Absence of thymus and parathyroids due to abnormal – Absence of IgA & IgG with normal/elevated IgM development of the 3rd and 4th pharyngeal pouches Transient Hypogammaglobulinaemia Inadequate T-helper cells lead to absence of antibodies Common Variable Hypogammaglobulinaemia Neonates develop hypocalcaemic tetany and repeated Selective IgG subclass deficiency chronic infections with viruses, fungi and protozoa Associated with other developmental conditions: – Cardiac defects, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcaemia (parathyroid hypoplasia) – ‘CATCH 22’ PRIMARY IMMUNE DEFICIENCY DISORDERS PRIMARY IMMUNE DEFICIENCY DISORDERS COMBINED (BOTH B- & T-CELLS) COMBINED (BOTH B- & T-CELLS) a. Severe Combined Immunodeficiency (SCID) Failure of stem cells to differentiate into T- and B-cells b. Other: Genetics: – Various genetic defects Hereditary ataxia-telangiectasia (Louis–Bar syndrome) – Inherited as either X-linked or autosomal recessive trait Wiskott-Aldrich Syndrome Pathogenesis: – Defect of both T- and B-cell immunity – Defective cell signaling – Defective IL-2 Clinical picture: – Increased susceptibility to all types of infections – Recurrent infections – Death at early age 16  2024/06/02 PRIMARY IMMUNE DEFICIENCY DISORDERS PRIMARY IMMUNE DEFICIENCY DISORDERS PHAGOCYTIC DYSFUNCTIONS PHAGOCYTIC DYSFUNCTIONS b. Functional defects involving chemotaxis, opsonisation, a. Neutropenia ( 1 month) Oral candidiasis Pulmonary TB Stage 4 Wasting PCP, CMV infection Disseminated TB Kaposi’s sarcoma Neurological problems. http://aidsetc.org/guide/hiv-classification-cdc-and-who-staging-systems 18  2024/06/02 Acute Chronic AIDS infection infection QUESTIONS OR COMMENTS? T: 051 401 9111 [email protected] www.ufs.ac.za 19