Immunodeficiency

Innate immunity

• Response to organisms not previously encountered
• Plasma proteins, complement system (alternative pathway), mannose-binding lectin, NK cells and some macrophage functions
• Acute phase reaction
  • Within hours of acute stress, get fall in Hb, serum iron and albumin with rise in CRP, ferritin, fibrinogen (raised ESR)

Adaptive immunity

• Characterised by specificity, memory, amplification and diversity
• Lymphocytes and antigen receptors on their surface
• Amplification and diversity regulated by cytokines and various lymphocyte surface molecules
  • IFN-gamma: Cell activation
  • IL-10: Regulation of immune reaction
  • TNF and lymphotoxins: Proinflammatory effects
• Antigen presentation
  • Major histocompatibility class I (HLA-A,B,C) and class II (HLA-DR, DP, DQ) molecules present antigens in a way as to trigger immune response
  • Class I MHC on nucleated cells and present endogenous peptides to antigen receptors (T cell receptors) of CD8+ T cells
  • Class II MHC present exogenous peptides on macrophages and monocytes and bind to antigen-specific surface antibodies on B cells and T cell receptors on CD4+ (helper) T cells

T cells and B cells

• CD8+ T cells have a cytotoxic effect on cells expressing specific antigens on Class I MHC molecules
• CD4+ T cells are activated by antigens on Class II MHC molecules and release cytokines and cell-surface molecules to trigger immune reaction (Helper T cells)
  • Also activate macrophages to phagocytose and destroy specific organisms via IFN-gamma
• Proliferating B cells (under activation from T helper Cd4+ cells) differentiate into plasma cells, which secrete immunoglobulins

Immunoglobulins and antibodies

• IgM: Large pentameric molecule. Primarily a bacterial agglutinator and activator of complement system
• IgA1 and IgA2: Produced at secretory surfaces and breast milk
• IgE: Mucosal surfaces also with important role against parasitic infection
• IgG1/IgG3: Activate complement system and bind to Fc receptors on phagocytic cells
• IgG2: Mainly active against polysaccharide antigens (such as bacterial cell wall)

Secondary antibody function

• Elimination of microorganisms via antibody function requires secondary effector mechanisms
• Antibody: Antigen complexes activate complement through the classical pathway
• Components of microorganisms can directly activate the complement system via the alternative pathway
• C3b is an important opsonin
• MAC lyses bacterial cell walls
• IgM, IgG1, IgG3 are also important opsonins to facilitate phagocytosis

Diversity of immune responses

• Viruses induce CD8+ T cell response
• Intracellular organisms (e.g. mycobacteria, protozoa) elicit CD4+ T cell response leading to macrophage activation
• Encapsulated bacteria induce opsonin antibody response
• Neisseria induces complement-activating antibody response, which lyses bacterial cell wall
• IL-2, IL-12 and IFN-gamma result in predominantly cellular immune response (Th1)
• IL-4 and IL-13 result in predominantly antibody-mediated immune response (Th2)

immunodeficiency

• Antibody deficiency
• Complement deficiency
• Cellular immunodeficiency
• Combined immunodeficiency
• Phagocyte dysfunction

Antibody deficiency

• Results in lack of opsonin activity and a propensity for infections from encapsulated bacteria (pneumococci, H. influenzae)
• Recurrent respiratory tract infections including sinusitis is classic
• Chronic echovirus infections of nervous system and some mycoplasmas seen in agammaglobulinaemia
• IgA deficiency specifically is usually compensated for by adequate IgM and IgG production

Antibody deficiency

• Primary antibody deficiency disorders
  • X-linked agammaglobulinaemia
  • HyperIgM immunodeficiency
  • Common variable immunodeficiency
  • IgA deficiency
• Secondary antibody deficiency
  • B-cell chronic lymphocytic leukaemia/lymphoma
  • Myeloma
  • Thymoma
  • Phenytoin – IgA deficiency
  • Intensive plasmapheresis

Cellular immunodeficiency

• Increased propensity to intracellular pathogens and latent infections that reactivate
• E.g. Mycobacteria, Salmonella, Shigella, Listeria, Candida, PCP, Cryptococci, Aspergillus, Toxoplasma, Cryptosporidia, HSV, CMV, VZV, EBV, molluscum contagiosum, JC virus

Cellular immunodeficiency

• Primary cellular immunodeficiency
  • DiGeorge syndrome (no thymus)
  • Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome
• Acquired cellular immunodeficiency
  • HIV
  • Hodgkin’s disease
  • T-cell lymphoma
  • Sarcoidosis
  • Thymoma
  • Intentional therapeutic immunosuppression

Complement deficiency

• Complement-mediated lysis of bacterial cell walls is crucial against Neisseria, Moraxella and Acinetobacter
• Primary complement deficiency
  • Deficiency of MAC components (C5-9) 
  • Deficiency in classical pathway components (C1,2,4)
• Acquired complement deficiency
  • Persistent activation of classical pathway e.g. Neisseria infection
  • SLE
  • Myeloma
  • Chronic AV shunt infections

Phagocyte defects

• E.g. neutropaenia
• Increased propensity to bacterial and fungal infection
• Specifically S. aureus, Gram-negative enteric bacteria, Candida and Aspergillus
• Fungal and yeast infections often become fungaemic in the setting of neutropaenia
• Often show limited local inflammation but overwhelming systemic infection
• Can treat with G-CSF

Phagocyte defects

• Primary phagocyte defects
  • Leukocyte adhesion deficiency syndrome type 1
  • Chronic granulomatous disease (ineffective oxidative killing mechanisms) with resultant recurrent abscesses, suppurative lymphadenitis and pneumonia from S. aureus/Aspergillus
• Acquired
  • Autoimmune neutropaenia
  • Chemotherapeutics
  • Cyclic neutropaenia
  • Myelodysplastic syndromes
  • Aplastic anaemia

Combined immunodeficiency disorders

• Primary combined immunodeficiency
  • X-SCID
• Acquired
  • Haematopoietic stem cell transplant: Antibody and cell-mediated immunity are impaired for 3-4 months post-transplant and often compounded by immunosuppressive therapy + steroids
  • Critical illness: Abnormal cellular immunity, Ig deficiency and impaired neutrophil function. 
  • Asplenia/hyposplenism: Crucial role in removal of opsonised microorganisms from blood and production of early antibody response to polysaccharide antigens of encapsulated bacteria by IgM memory B cells. Important organisms include S. pneumoniae, H. influenzae, meningococcus, GAS, Capnocytophagia canimorsus, Salmonella, Enterococcus and Bacteroides

Last Updated on October 2, 2020 by Andrew Crofton