L16 Immunodeficiency diseases Flashcards
When are infections more likely to be significant
- Infections are verified rather than simply reported
- Organisms can be identified
- End-organ damage has occurred
General classification of immunodeficiency
- Secondary immunodeficiency
- Primary immunodeficiency syndrome (PID)
Features of 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
- Infections eg HIV
Features of 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 infections)
Effect of CD4 T cell defects on B cells
- CD4 T cell defects affect B cells, as T cell help is needed 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
What is immunodeficiency predominantly caused by
- 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 anti-microbials, but response may be sub-optimal and long courses required
- If untreated, leads to irreversible lung damage(bronchiectasis)
Physiological cause of antibody deficiency
Physiological:
- Transient hypogammaglobulinemia of infancy
Secondary cause of antibody deficiency
IgG loss:
- Renal (nephrotic syndrome)
- Skin (extensive burns)
Impaired production:
- Immunosuppressive drugs
Primary causes of antibody deficiency
- X-linked agammaglobulinemia
- X-linked hyper-IgM syndrome
- (Common variable immunodeficiency)
- 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 - 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 and IgA, raised(or normal) IgM
- Recurrent bacterial infections
- The immunological lesion actually resides on the T cell (CD40 ligand, interaction with CD40 on B cells required for affinity maturation)
When does X-linked hyper IgM syndrome present usually
- Presents age 3-6 months
Production of high affinity IgG antibodies - X-linked hyper-IgM syndrome
Naive B cell, surface IgM –> meets antigen in lymphoid tissue –> somatic hypermutation and class-switch recombination –> high affinity IgG antibodies
