IMMUNE DEFICIENCY lec 1 and 2

د. علياء طب 6\3\2018

عدد الاوراق ( 5 ) م\3\موصل LEC: 1+2
IMMUNE DEFICIENCY
Definition: Defects in immune function.
1-Primary (rare): genetically determined deficiencies, mostly present in childhood or adolescence
2-Secondary (common)
Consequences:
Recurrent infections, autoimmunity and susceptibility to malignancy

Presenting problems in immune deficiency

Frequent, severe infections or infections caused by unusual organisms or at unusual sites.
Warning signs of primary immune deficiency: The presence of ≥ 2 warning signs may indicate an underlying primary immunodeficiency:
• ≥ 4 new ear infections within 1 yr
• ≥ 2 serious sinus infections within 1 yr
• ≥ 2 mths on antibiotics with little effect
• ≥ 2 pneumonias within 1 yr
• Failure of an infant to gain weight or grow normally
• Recurrent, deep skin or organ abscesses
• Persistent thrush in mouth or fungal infection on skin
• Need for intravenous antibiotics to clear infections
• ≥ 2 deep-seated infections, including septicaemia
• A family history of primary immune deficiency


Baseline investigations when immune deficiency is suspected:
1-full blood count with white cell differential,
2-acute phase reactants (CRP),
3-renal and liver function tests,
4-serum immunoglobulins with protein electrophoresis to exclude secondary causes of hypogammaglobulinaemia
5-Additional microbiological, virological and radiological tests may be appropriate.

A- Primary phagocyte deficiencies

Usually present with recurrent bacterial and fungal infections which may affect unusual sites.
Leucocyte adhesion deficiencies:They are characterised by recurrent bacterial infections with high blood neutrophil counts but sites of infection lack pus or other evidence of neutrophil infiltration.
Chronic granulomatous disease:This is caused by mutations in the genes encoding the NADPH oxidase enzymes, which results in failure of oxidative killing. Infections most commonly involve the lungs, lymph nodes, soft tissues, bone, skin and urinary tract, and are characterised histologically by granuloma formation.
Defects in cytokines and cytokine receptors: Defects of cytokines such as IFN-γ, IL-12 or their receptors also result in failure of intracellular killing, with particular susceptibility to mycobacterial infections

B-Complement pathway deficiencies

Present with recurrent infection with encapsulated bacteria, particularly Neisseria species, reflecting the importance of the membrane attack complex in defence against these bacteria.
In addition, genetic deficiencies of the classical complement pathway (C1, C2 and C4) are associated with a high prevalence of autoimmune disease, particularly systemic lupus erythematosus.
Measurement of Complement C3 and C4.
Screening for complement deficiencies is performed using more specialised functional tests of complement-mediated haemolysis,
Lifelong prophylactic penicillin to prevent meningococcal infection is recommended.

C-Primary deficiencies of the adaptive immune system

Primary T-lymphocyte deficiencies:
1-DiGeorge syndrome: This results from failure of development of the 3rd/4th
pharyngeal pouch, The immune deficiency is characterised by very low numbers of circulating T cells, despite normal development in the bone marrow.
2-Bare lymphocyte syndromes:These are caused by absent expression of HLA molecules within the thymus, associated with systemic vasculitis caused by uncontrolled activation of NK cells.
3-Autoimmune lymphoproliferative syndrome:This is caused by failure of normal lymphocyte apoptosis leading to non-malignant accumulation of autoreactive cells. This results in lymphadenopathy, splenomegaly and a variety of autoimmune diseases.
T lymphocyte function and dysfunction


Combined B- and T-lymphocyte immune deficiencies:
Severe combined immune deficiency (SCID) is caused by defects in lymphoid precursors and results in combined failure of B- and T-cell maturation.
The absence of an effective adaptive immune response causes récurrent bacterial, fungal and viral infections soon after birth.
HSCT is the only current treatment,
Gene therapy is under investigation.

Primary antibody deficiencies: characterised by recurrent bacterial infections, particularly of the respiratory and gastrointestinal tract. The most common causative organisms are encapsulated bacteria, such as Strep. pneumoniae and H. influenzae:
1-Selective IgA deficiency: is the most common primary immune deficiency,
affecting 1 : 600 northern Europeans, 30% of individuals experience recurrent mild respiratory and gastrointestinal infections.
2-Common variable immune deficiency (CVID):It is characterised by low serum IgG levels and failure to make antibody responses to exogenous pathogens. Paradoxically, antibody mediated autoimmune diseases, such as autoimmune haemolytic anaemia, are common. CVID is also associated with an increased risk of malignancy, particularly lymphoproliferative disease.
3-Specific antibody deficiency or functional IgG antibody deficiency: defective antibody responses to polysaccharide antigens.

B Lymphocyte and antibodies deficiencies

Investigations:
Specific antibody responses to known pathogens can be assessed by measuring IgG antibodies against tetanus, H. influenzae and Strep. pneumoniae (most patients will have been exposed to these antigens through infection or immunisation).
If specific antibody levels are low, immunisation with the appropriate killed vaccine should be followed by repeat antibody measurement 6–8 weeks later; failure to mount a response indicates a defect in antibody production.
Management:The mainstay of treatment is life-long immunoglobulin replacement therapy, derived from pooled plasma and contains IgG antibodies to a wide variety of common organisms.
Immunoglobulin replacement may be administered either intravenously or subcutaneously, often by the patient, with the aim of maintaining IgG levels within the normal range.
Immunisation is generally not effective because of the defect in IgG antibody production.
Live vaccines should be avoided in all primary immune deficiencies.


Immune deficiencies and common patterns of infection

Secondary immune deficiencies

Secondary immune deficiencies are much more common than primary immune deficiencies.
CAUSES:
Physiological; Pregnancy, aging , prematurity.
Infection; HIV, Measles, Mycobacterium infection.
Iatrogenic; Immunosuppressive therapy, Antineoplastic agents, Corticosteroids, Stem cell transplantation, Radiation injury, Some anti-epileptic agents.
Malignancy; B-cell malignancies including leukaemia, lymphoma and myeloma, thymoma.
Biochemical and nutritional disorders; Malnutrition, Renal insufficiency/dialysis, Diabetes mellitus, Specific mineral deficiencies, e.g. iron, zinc.
Other conditions; Burn, Hyposplenism.

Lec 2

AUTOIMMUNE DISEASE
AUTOIMMUNE DISEASE
Definition of Autoimmunity: the presence of immune responses against self tissues.
Pathophysiology of autoimmunity:
Failure of immunological Tolerance.
Immunological Tolerance: the process by which the immune system recognises and accepts self tissue. Autoreactive cell (when T and B lymphocytes that recognise self antigens) are eliminated before they differentiate into full immunocompetent cells, inevitably some autoreactive cells evade deletion and reach the peripheral tissues, where they are controlled by peripheral tolerance mechanisms.
Autoimmune diseases develop when self-reactive lymphocytes escape from these tolerance mechanisms and become activated


The spectrum of autoimmune disease
Organ-specific : Immune response directed against localized antigens.
Graves’ disease,
Hashimoto’s thyroiditis,
Pernicious anaemia,
Type 1 diabetes,
Multiple sclerosis,
Pemphigus vulgaris and Bullous pemphigoid,
Idiopathic thrombocytopenic purpura,
Autoimmune haemolytic anaemia,
Myasthenia gravis,
Primary antiphospholipid syndrome,
Rheumatoid arthritis,
Dermatomyositis,
Primary biliary cirrhosis,
Autoimmune hepatitis.

The spectrum of autoimmune disease

Multisystem: Immune response directed to widespread target antigens.
Systemic sclerosis
Mixed connective tissue disease
SLE


Factors predisposing to autoimmune disease
Autoimmune diseases are much more common in women than in men, for reasons which remain unclear.
Genetic: Most autoimmune diseases have multiple genetic determinants, associated with variation at specific HLA loci, or other important susceptibility genes include those determining cytokine activity, co-stimulation and cell death.
Acquired: infection, drug. e.g. Acute rheumatic fever following streptococcal infection or reactive arthritis following bacterial infection, the mechanisim is due to cross-reactivity between the infectious pathogen and self antigens (molecular mimicry), and release of sequestered antigens, which are not usually visible to the immune system. Other e.g. the metabolic products of the anaesthetic agent halothane bind to liver enzymes, resulting in a structurally novel protein. This is recognised as a new (foreign) antigen by the immune system, and the autoantibodies and activated T cells directed against it may cause hepatic necrosis.

Classification of autoimmune diseases

Classified by organ involvement,
Classified by the predominant mechanism responsible for tissue damage.
Type I hypersensitivity is relevant in allergy but is not associated with autoimmune disease.
Type II hypersensitivity, injury is localised to a single tissue or organ and is mediated by specific autoantibodies. E. g. of Auto immune diseases are Autoimmune haemolytic anaemia, Idiopathic thrombocytopenic purpura, Goodpasture’s disease.

Classification of autoimmune diseases

Type III hypersensitivity is a generalised reaction resulting from immune complex deposition which initiates activation of the classical complement cascade, as well as recruitment and activation of phagocytes and CD4+ lymphocytes. The site of immune complex deposition is determined by the relative amount of antibody, size of the immune complexes, nature of the antigen and local haemodynamics. Generalised deposition of immune complexes gives rise to systemic diseases such as SLE.
Type IV hypersensitivity, activated T cells and macrophages mediate phagocytosis and tissue damage.e.g. type 1 diabetes and Hashimoto’s thyroiditis.
Investigations in autoimmunity
Autoantibodies: A number of autoantibodies can be identified in the laboratory and are used in disease diagnosis and monitoring,
Measures of complement activation: Quantitation of complement components may be useful in the evaluation of immune complex-mediated diseases.
Cryoglobulins: Cryoglobulins are antibodies directed against other immunoglobulins, and which form immune complexes that precipitate in the cold.