Immune Deficiencies and Autoimmunity Flashcards
What is immunodeficiency?
- Partial/full impairment of immune system function/development
- Body unable to effectively resolve infections - high risk of recurrence
- Associated with autoimmunity, lymphomas, other cancers
What is the difference between primary and secondary immunodeficiencies?
- PRIMARY - congenital
- SECONDARY - acquired from disease/environmental factors
What are the categories of primary immunodeficiencies?
- Antibody deficiencies
- Combined immunodeficiencies
- Phagocytic cell disorders
- Complement deficiencies
- Disorders of immune regulation
What are the features of the following immunodeficiencies:
- B cell deficiencies
- T cell deficiencies
- Innate immune deficiencies
- B cell - reduced serum Ig levels and absent/reduced follicles in lymphoids. Involved in pyogenic bacterial infections
- T cell - reduced in lymphoids - reduced reactions to antigens. Involved in viral infections
- Innate immune deficiencies - dependent on which component of innate immunity defective
What are the clinical mainfestations of immune deficiencies?
- GI, haematologic and infectious diseases
- Autoimmune/rheumatic diseases - arthritis and SLE
Give examples of infectious diseases someone with immune deficiencies may suffer from.
- Recurrent sinopulmonary infections e.g sinusitis, bronchitis and pneumonia most common presenting manifestations
- Recurrent sysetmic infections e.g bacteremia and meningitis
What is the most common type of presenting infections in patients with primary antibody deficiencies?
RESPIRATORY
When are autoimmune/rheumatic diseases most common?
- Selective IgA deficiency
- CVIDs
- Deficiencies of complement system
What are some types of primary antibody deficiencies (humoral immunity deficiencies)?
- X-linked agammaglobulinema (XLA), Bruton’s
- CVIDs
- Selective IgA deficiency
- IgA and IgG subclass deficiency
- Autosomal recessive hyper IgM syndromes
- BCR deficiencies
Describe X-linked agammaglobulinemia. PART 1
- Low immunoglobulins and absent B cells
- Mutation in Bruton’s tyrosine kinase Btk (encoded by BTK) on X chromosome - in B cell development/maturation
Describe X-linked agammaglobulinemia. PART 2
- Maturation stops at pre-B cell stage - no mature B cells/antibodies
- Recurrent sinopulmonary infections with encapsulated bacteria
- Treatment with Ig replacement therapy
Describe CVIDs
- Low IgG and IgA and reduced/normal IgM
- Normal/low number of B cells
- Recurrent pulmonary manifestations - pneumonia/asthma/bronchiestasis/pulmonary fibrosis
- Many patients lead normal lives - receive replacement Ig therapy
Describe selective IgA deficiency.
- Very low IgA in serum
- Normal IgG and IgM levels
- Recurrent sinopulmonary disorders, allergies and autoimmune disorders
- Maturation defect of B cells to produce IgA - cannot develop into IgA-secreting plasma cells
Describe SCID PART 1
- Absence of T cells and/or B cells and NK cells
- More common in males (X-linked SCID very common)
- Mutation of gene encoding for common gamma chain in several cytokine receptors i.e those for IL-2/4/7/9/15
Describe SCID PART 2
- Children with SCID usually have severe infections - die during 1st year of life
- Grafting of viable immunocompetent cells - offers hope of permanent restoration of immune responsiveness
- Human stem cell transplantation - treatment
- Tested using TREC test - test for presence of TREC which indicates T cell maturation. Reduced in SCID
Describe DiGeorge syndrome. PART 1
- Arise from defect in thymus embryogenesis
- Majority - partial monosomy of 22q11.2
- T cell immunodeficiency - variable expression of disease
Describe DiGeorge syndrome. PART 2
- B cells present. T-dependent B cell responses
- Poorly developed or functioning thymus
- Underdeveloped parathyroid glands
- Low set ears, midline facial clefts, congenital heart disorders, delay in development
- Fatal for children with no T cells - transplantation of stem cells/thymic tissue
What are congenital immunodeficiencies caused by?
- Defects in lymphocyte maturation
Give examples of defects in innate immunity.
- PHAGOCYTE DEFICIENCIES - example CGD, leucocyte adhesion deficiency
- COMPLEMENT DEFICIENCY
- DEFECTS IN NK cells/OTHER LEUCOCYTES - inherited defects in TLR pathways/type 1 interferons
Describe CGD. PART 1
- X-linked
- Severe type of defect in neutrophil function
- Inability of phagocytes to generate H2O2 - mutations in one of proteins in NADPH oxidase.
- Microbicidal function impaired - bacteria/ fungi not killed during phagocytosis.
Describe CGD. PART 2
- Leads to granuloma formation
- Severe recurrent infections resulting in pneumonia and skin/bone/organ abscesses
- Treatment by antibiotics/antifungals
Describe complement deficiencies.
- C1q, C4 and C2 deficiency - lupus-like syndrome of flush, glomerulonephritis, fever. C1q deficiency - recurrent pyogenic infections
- C3 deficiency - present in pneumonia, septicaemia and meningitis
What can cause secondary immunodeficiencies? PART 1
- HIV - depletion of CD4+ T helper cells
- Irradiation/chemotherapy - decreased precursors for leucocytes
- Involvement of bone marrow by cancers - reduced site of leucocyte development
What can cause secondary immunodeficiencies? PART 2
- Protein-calorie malnutrition - metabolic deficiencies inhibit lymphocyte maturation/function
- Spleen removal - decreased phagocytosis
Describe HIV.
- HIV retrovirus synthesise dsDNA - integrate into host genome for viral replication
- Attacks and destroys T helper cell - attach via CD4 receptor
- Increased CD8 cells - attack host
- Susceptible to opportunistic infections
Describe the HIV life cycle.
Describe the pathogenesis of HIV during acute infection.
- HIV infects CD4+ T cells, migrates to lymphoid tissues
- Rapid increase in replication as CD4+ T cells are destroyed by virus. Macrophages are also infected.
- Dendritic cells present antigens and activate HIV-specific CD8+ cytotoxic T cells.
- Viral load reduces and CD4+ T cells increase.
Describe the pathogenesis of HIV during chronic infection.
- CD4+ T cells decline slowly. Viral load remains stable, HIV-specific antibodies are generated
- Neutralising antibodies begin to appear only after about 3-6 months and HIV replication continues
- Immune evasion exhausts the immune system leading to opportunistic infection and AIDS
