T1 L24. Immunodeficiency diseases (MTz).pptx

Module 204 Immunology Immunodeficiency Diseases Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover – Immunodeficiency as a clinical diagnosis – Classification of immunodeficiency: primary vs secondary, (T) cell mediated vs antibody vs combined – Tr...

Module 204 Immunology Immunodeficiency Diseases Dr Michael D Tarzi Senior Lecturer&Honorary Consultant Immunologist Aims • This lecture will cover – Immunodeficiency as a clinical diagnosis – Classification of immunodeficiency: primary vs secondary, (T) cell mediated vs antibody vs combined – Transient hypogammaglobulinemia of infancy – Prototype antibody deficiency syndromes: XLA, hyper-IgM syndrome – Prototype cell mediated immunodeficiency syndromes: DiGeorge, SCID – Terminal complement pathway deficiency Learning Objectives • You should be able to: – Discuss what is meant by the term’immunodeficiency’, and outline some of the difficulties of this term – Describe a classification system for immunodeficiency – Give examples of secondary immunodeficiency, particularly the immunology of older life – Explain ‘transient hypogammaglobulinemia of infancy’ – Outline the key clinical features of antibody deficiency and describe the immunology of XLA and X-linked hyper-IgM syndrome – Outline the key clinical features of (T) cell-mediated immunodeficiency – Describe the clinical features and immunology of SCID and DiGeorge syndrome – Explain the clinical features and immunology of terminal complement deficiency What do we mean by immunodeficiency? Infections that are....... Opportunistic Unusual Unusually severe, protracted or not responding to standard therapy Frequent What do we mean by immunodeficiency? Infections that are....... Opportunistic Unusual Unusually severe, protracted or not responding to standard therapy What do we mean by unusual or severe? What do we mean by frequent? What about co-factors that may influence infection frequency? Frequent What do we mean by immunodeficiency? Infections that are....... Opportunistic Unusual Unusually severe, protracted or not responding to standard therapy Frequent So there is no definitive definition....... •The diagnosis is largely descriptive •Infections more likely to be significant if........ •Infections are verified rather than simply reported •Organisms can be identified •End-organ damage has occurred General classification of immunodeficiency • • Secondary immunodeficiency • Immune defect is secondary to another disease process • Very common • Extremes of age • Malignancies (esp myeloma, lymphoma) • Metabolic eg diabetes • Drugs eg chemotherapy, steroids • Infection eg HIV Primary immunodeficiency syndrome (PID) – Immune defect is intrinsic to the immune system itself – Rare – Often genetic, but not always – Over 100 characterised PIDS – Mostly are fairly ‘new’ diseases • Fatal in pre-antibiotic era • Characterisation required developments in technology Immunological classification of immunodeficiency Human immune system Innate Variety of manifestations – depends on problem Adaptive B cells Antibody-deficiency (or humoral immunodeficiency) predominantly bacterial infections of the respiratory tract T cells Cellular immunodeficiency; predominantly viral, fungal and mycobacterial More notes on immunodeficiency........ • CD4 T cell defects affect B cells, as T cell help is need for B cell maturation • This is particularly marked in infants; less marked in adults, who have already matured their B cells • Immunodeficiency syndromes affecting both antibody production and T cells are called combined immunodeficiencies • In addition to infections, many immunodeficiency syndromes manifest with immune dysregulation: uncontrolled inflammation, autoimmune diseases Aging and immunity (‘immunosenscence’ ‘A combination of age-related changes in the immune system that result in greater susceptibility to infection and reduced response to vaccination’ Some immunological aspects of immunosenescence • Thymic involution • Telomere shortening in stem cells reduces both quality and quantity of leucocyte output • Reduced T and B cell receptor diversity • Reduced vaccine responses • Reduced neutrophil function • Reduced self-tolerance; inflammation switches from protection to damage • Expansion of T cell pool responding to cytomegalovirus (current research focus) But it’s complicated……. • Elderly clearly more susceptible to infection, but immunity itself is not the only factor: – Reduced mobility – Nutrition – Wound healing – Co-morbidities (COPD, CCF, DM, cancer, depression etc) – Reduced physiological reserve • All of these increase risk of infection AND risk of poor outcome from infection • See VZV immunisation slides: clear that older people can make a response to a specifically tailored immune booster Predominantly antibody deficiency • Low IgG; other isotypes may be affected, but low IgA/ M with normal IgG is rarely significant • Manifests with recurrent pyogenic infections of the upper and lower respiratory tract • Sometimes gut infections in addition • Infections typically respond to antimicrobials, but response may be suboptimal and long courses required • If untreated, leads to irreversible lung damage (bronchiectasis) Some causes of antibody deficiency • Physiological – Transient hypogammaglobulinemia of infancy (see next slide) • Secondary – IgG loss: • Renal: nephrotic syndrome • Skin: extensive burns – Impaired production: • Immunosuppressive drugs • Primary – X-Linked agammaglobulinemia – X-Linked hyper-IgM syndrome – (Common variable immunodeficiency – module 302) – Many others that are beyond scope Maturation of antibody production • In healthy infants there is normally a period of relative antibody deficiency around 6 months known as ‘transient hypogammaglobulinemia of infancy; this is a physiological state but can be correlated with increased infections • Infants with antibody deficiency usually present after 3-6 months; up until this time they are protected by maternal IgG antibody XLA – a prototype antibody deficiency syndrome • Signalling via Bruton’s tyrosine kinase (btk) required for signal transduction at pro-B stage • Maturation arrest occurs if absent: no heavy chain rearrangement, no B cells leave marrow, no immunoglobulin production • Disease is called X-linked agammaglobulinaemia (XLA); also known as Bruton’s disease, Btk deficiency or Bruton’s XLA X-Linked hyper IgM syndrome (CD40L deficiency) • Failure of B cell maturation from primary to secondary • Low IgG & IgA, raised (or normal) IgM • Recurrent bacterial infections • Presents age 3-6 months • The immunological lesion actually resides on the T cell – CD40 ligand (also known as CD154) – Interaction with CD40 on B cells required for affinity maturation X-Linked Hyper-IgM syndrome Naive B cell, surface IgM Meets antigen in lymphoid tissue Somatic hypermutati on Class-switch recombinati on High affinity IgG NOTE: some of these patients have an associated cellular immunodeficiency, see Treating antibody deficiency • • • • Early recognition before lung damage occurs Aggressive treatment of intercurrent infections Replace immunoglobulin Long-term suppressive anti-microbials Cellular immunodeficiency • Poor terminology; used to mean CD4 T cell deficiency • When congenital, antibodies will also be affected (combined immunodeficiency) • Manifests particularly with: – Opportunistic infection – Viral infection – Fungal infection – Mycobacterial infection • Classic secondary cause is HIV infection Some conditions seen in cellular immunodeficiency, particularly advanced HIV Severe combined immunodeficiency • • • • Rare, life-threatening primary immunodeficiency Absent T cells B cells may be present, but are non-functional All basically present in a similar fashion – Usually soon after birth – Rash (graft versus host - maternal lymphocyte engraftment) – Failure to thrive – Chronic diarrhoea – Infections, especially opportunistic • Bacterial • Mycobacterial (esp BCG) • Viral (esp CMV, EBV) • Fungal (PCP, oral thrush) Severe combined immunodeficiency (SCID) • Variety of molecular causes, only three considered this year: – Common gamma chain deficiency – JAK3 deficiency – RAG1/2 deficiency Common gamma chain deficiency and JAK3 deficiency Common gamma-chain deficiency • X-linked SCID • Common gamma chain forms part of membrane receptor for several cytokines, some of which are required for T cell maturation • Absent T cells • B cells present but non• JAK-3 deficiency functional deficiency • Autosomal recessive SCID • JAK-3 is downstream of common gamma chain; deficiency likewise prevents signalling RAG 1&2 deficiency • An autosomal recessive form of SCID • RAG 1/2 required for somatic recombination events between V(D)J gene segments • No RAG1/2 means no T and B cell receptors SCID therapy Bubbles: no longer used Stem cell transplant • Stem cells harvested from HLAmatched donor: Given to recipient by infusion Engraft in bone marrow RECONSTITUTION of T and B cells See module 302 for gene therapy as an alternative Another combined immunodeficiency syndrome: DiGeorge syndrome • Failure migration 3th/ 4th branchial arches • Full phenotype: – Absent parathyroids (low calcium, tetany) – Cleft palate – Congenital heart defects – Thymic aplasia (low T cell numbers, immunodeficiency) • Most patients have microdeletions chromosome 22 • Variable presentation – Huge spectrum of immunodeficiency from mildSCID-like – Autoimmunity is also common – Patients with 22q11 microdeletions may have none of the above, all of the above and anything inbetween Terminal complement deficiency • Deficiency of terminal complement components C5-C9 leads to specific susceptibility to Neisseria Species • Otherwise immunologically robust • Diagnose by functional complement assays (speak to your