Overview
This lecture covers immunodeficiency, contrasting rare, genetically-caused primary immunodeficiencies with common, acquired secondary immunodeficiencies. It works through the major categories of primary immunodeficiency by the arm of immunity affected (antibody, complement, phagocyte, T cell), then covers the common causes of secondary immunodeficiency and the molecular targets of the immunosuppressive drugs used clinically.
Primary immunodeficiency: classification and clinical clues
- Primary immunodeficiency is rare and genetic; secondary immunodeficiency is common, caused by immunosuppressive/cytotoxic therapy, infectious agents (e.g. measles, HIV), malignancy/myelodysplasia, or environmental causes (e.g. starvation).
- Suspect primary immunodeficiency with a history of repeated infections (same or similar pathogens), persistent infections, or severe infections.
- The type of infection points to the defect:
- Pyogenic bacterial infection suggests a defect of antibody, complement, or phagocyte function.
- Fungal skin infection or severe viral infections suggest a T cell defect.
- Age of presentation is a further clue:
- <6 months: severe immunodeficiency, T cell defects.
- 6 months-5 years: maternal antibody has waned, antibody or phagocyte defects.
-
5 years: common variable immunodeficiency (CVID), specific antibody deficiency, complement deficiency.
- Inherited immunodeficiencies are caused by recessive gene defects, many on the X chromosome; they can affect adaptive or innate immunity, and development or function. IgA deficiency is the most common (prevalence 1:100-1:1000). Studying them illuminates normal pathways of immune defence and redundancy.
Antibody (B cell) deficiencies
- Antibody clears extracellular infections via opsonisation of encapsulated bacteria (enabling phagocytosis) and neutralisation of viruses.
- Antibody deficiency phenotype: recurrent sinus and pulmonary infections, pyogenic bacteria and some viruses.
- Treatment: antibiotics, and monthly intravenous immunoglobulin as antibody replacement.
Specific disorders:
- Bruton’s X-linked agammaglobulinaemia: mutation in Btk (Bruton’s tyrosine kinase). Btk is expressed in both B cells and monocytes, but only B cells are functionally defective. B cell maturation is arrested at the pre-B cell stage, resulting in absence of antibody.
- Hyper IgM syndrome: normal numbers of B cells with high levels of IgM, but other antibody isotypes (e.g. IgG) are absent, due to impaired class switching. This can result from a defect in B cell activation (e.g. CD40) or in the class-switching machinery itself (e.g. activation-induced cytidine deaminase, AID).
- Common variable immunodeficiency (CVID): normal numbers of B cells that are functionally deficient, due to a block in the B cell maturation and differentiation process. Predominantly a humoral immunodeficiency, with deficiency in IgM, IgG and IgA. Less severe than some other immunodeficiencies; many patients are diagnosed in adulthood.
- Selective IgA deficiency: the most common primary antibody deficiency (prevalence 1:100-1:1000). Total or partial IgA deficiency caused by failure of B cells to terminally differentiate into IgA-secreting plasma cells. Usually asymptomatic, but associated with increased infections, drug allergy, and autoimmune or atopic disease compared with controls.
Complement deficiencies
- C1-C4 are important for elimination of immune complexes and apoptotic cells; deficiency is associated with autoimmune disease, e.g. SLE.
- Defective C3, or defective activation of C3, produces a similar spectrum of infections to humoral immunodeficiencies, with susceptibility to pyogenic infections, e.g. S. pneumoniae.
- Mannose-binding lectin (MBL) deficiency is relatively common (~5%) and mild, causing an excess of bacterial infection in early childhood.
- Defects in the membrane attack complex (C5-C9) have more limited effects, with susceptibility specifically to Neisseria species (a 10,000x increased risk).
Phagocyte deficiencies
- Total absence of neutrophils is incompatible with survival.
- Defects of neutrophil production (neutropaenias): severe congenital neutropaenia requires bone marrow transplant for survival.
- Defects of phagocyte function fall into two groups: defects in phagocyte migration, and defects in bacterial killing.
- Migration defects: reduced rolling adhesion (lack of sialyl-Lewis^x antigen) or defects in tight adherence (deficiencies in the common leukocyte integrin β2 subunit) prevent neutrophil migration to sites of infection. Resulting infections are resistant to antibiotic therapy and persist despite an otherwise effective adaptive immune response.
- Chronic granulomatous disease (CGD) – a defect in bacterial killing: a defect in production of reactive oxygen species (ROS), due to deficiency in glucose-6-phosphate dehydrogenase (G6PDH), NADPH oxidase, or myeloperoxidase (MPO). Phagocytes are unable to kill ingested bacteria, leading to granuloma formation; patients are highly susceptible to bacterial and fungal infections.
The diagrams of the ROS-production pathway and of the phagocytosis/granuloma-formation sequence for CGD could not be viewed (source PDF corrupted), so the exact order of steps and connections between the labelled components (NADP+, G6PDH, ROS; neutrophil, phagosome, microbe survival, defective killing mechanism, granuloma formation) are not confirmed beyond the points above.
T cell deficiencies: Severe Combined Immunodeficiency (SCID)
- SCID results in no cell-mediated immune responses and no T cell-dependent antibody responses.
- Causes severe opportunistic infections; affected infants normally die in the first year of life unless given IVIG and bone marrow transplantation.
- SCID demonstrates the central role of T cells in the adaptive immune response to virtually all pathogens.
- Molecular defects underlying SCID fall into categories including defects in cytokine signalling, defects in purine metabolism, defects in antigen receptor gene rearrangement, and defects in signalling from the T cell receptor. [slide does not elaborate further on these categories]
Secondary immunodeficiency: causes
Secondary immunodeficiency is common. Its causes include:
- Malnutrition
- Malignancy and myelodysplasia
- Iatrogenic causes: splenectomy, prosthetic implants
- Infection, e.g. HIV/AIDS, measles, post-sepsis
- Cytotoxic drugs
- Immunosuppressive drugs
The diagram grouping these causes around "secondary immunosuppression" could not be viewed (source PDF corrupted), so the exact structure/connections shown are not confirmed beyond the list of causes above.
Immunosuppressive drugs
- Commonly used in solid organ transplant recipients, autoimmune disease, and inflammatory disease.
- Mechanisms of action: inhibition of T cell activation, inhibition of lymphocyte proliferation, lymphocyte depletion, and inhibition of specific cytokines/cytokine receptors.
T cell activation and its targets
- T cell activation requires three signals: Signal 1 is the T cell receptor-MHC interaction; Signal 2 is co-stimulation (CD28-CD80/86, CD154-CD40); Signal 3 is cytokines (e.g. IL-12).
- T cell proliferation is IL-2 dependent.
Drug classes and mechanisms
- Calcineurin inhibitors (e.g. cyclosporine, tacrolimus): inhibit TCR signalling by blocking the NFAT signalling pathway, blocking IL-2 production; minimal effect on B cells or myeloid cells.
- CTLA-4 fusion protein immunoglobulins (belatacept, abatacept): inhibit co-stimulation by blocking the interaction between CD80/86 and CD28.
- Corticosteroids: inhibit the transcription factors AP-1 and NFκB, reducing expression of IL-2 and multiple other cytokines; have multiple other effects.
- mTOR inhibitors (e.g. sirolimus, everolimus): inhibit cytokine signalling by blocking IL-2 signalling, thereby inhibiting proliferation.
- Azathioprine (a purine analogue): inhibits purine synthesis, which is required for nucleic acid synthesis, thereby inhibiting proliferation.
- Immunosuppressive monoclonal antibodies are classified as depleting or non-depleting.
The figure classifying monoclonal antibodies as depleting vs non-depleting could not be viewed (source PDF corrupted), so specific drug names and their targets within each category are not recovered.
- Newer therapies target specific cytokines/cytokine receptors in immune-mediated inflammatory diseases; the slide’s figure of these targets was presented as illustrative only, with no detail required.
Self-test
- Distinguish primary from secondary immunodeficiency in terms of frequency and typical cause.
- Describe the clinical clues that should prompt suspicion of a primary immunodeficiency, including how age at presentation points to different defects.
- What pattern of infection points to a defect in antibody, complement, or phagocyte function, versus a defect in T cell function?
- Describe the two main functions of antibody in defending against extracellular infections.
- Describe the clinical phenotype and treatment of antibody deficiency.
- Describe the molecular defect underlying Bruton’s X-linked agammaglobulinaemia and explain why it selectively affects B cells despite Btk being expressed in monocytes too.
- Describe the defect in Hyper IgM syndrome and its two possible molecular causes.
- Distinguish common variable immunodeficiency (CVID) from Bruton’s agammaglobulinaemia in terms of B cell numbers and typical age at diagnosis.
- Describe selective IgA deficiency, including its frequency, underlying defect, and clinical presentation.
- Describe the clinical consequences of deficiency in C1-C4, in C3, and in the membrane attack complex (C5-C9).
- Which organism is characteristic of membrane attack complex deficiency, and by how much is the risk of infection increased?
- Describe the two categories of phagocyte function defect, giving an example mechanism for each.
- Describe the molecular defect and clinical consequences of chronic granulomatous disease.
- Describe the presentation and management of severe combined immunodeficiency (SCID).
- List the common causes of secondary immunodeficiency.
- List the four mechanisms by which immunosuppressive drugs act.
- Describe the three signals required for T cell activation and their relationship to IL-2-dependent proliferation.
- Describe the mechanisms of action of calcineurin inhibitors and CTLA-4 fusion proteins.
- Describe the mechanisms of action of corticosteroids, mTOR inhibitors, and azathioprine as immunosuppressants.
- A patient presents in adulthood with recurrent sinus infections, low IgM, IgG and IgA, but normal B cell numbers. Which primary immunodeficiency is most likely, and how does it differ from Bruton’s agammaglobulinaemia?
Answers
Reveal answers
- Primary immunodeficiency is rare and genetic (usually recessive, often X-linked); secondary immunodeficiency is common, caused by immunosuppressive/cytotoxic therapy, infectious agents (e.g. measles, HIV), malignancy/myelodysplasia, or environmental causes (e.g. starvation).
- Suspect it with repeated, persistent, or severe infections. Age gives further clues: <6 months suggests severe immunodeficiency/T cell defects; 6 months-5 years suggests antibody or phagocyte defects (maternal antibody has waned); >5 years suggests CVID, specific antibody deficiency, or complement deficiency.
- Pyogenic bacterial infection suggests a defect of antibody, complement, or phagocyte function; fungal skin infection or severe viral infections suggest a T cell defect.
- Opsonisation of encapsulated bacteria (enabling phagocytosis), and neutralisation of viruses.
- Phenotype: recurrent sinus and pulmonary infections with pyogenic bacteria and some viruses. Treatment: antibiotics and monthly intravenous immunoglobulin (antibody replacement).
- Mutation in Btk (Bruton’s tyrosine kinase). Although Btk is expressed in both B cells and monocytes, only B cells are functionally defective; B cell maturation is arrested at the pre-B cell stage, resulting in absence of antibody.
- Normal numbers of B cells with high IgM, but other isotypes (e.g. IgG) are absent, due to impaired class switching. This can arise from a defect in B cell activation (e.g. CD40) or in the class-switching machinery (e.g. AID).
- In CVID, B cell numbers are normal but functionally deficient due to a block in maturation/differentiation, with deficiency across IgM, IgG and IgA; it is less severe and often diagnosed in adulthood. In Bruton’s agammaglobulinaemia, B cell maturation is arrested at the pre-B cell stage, so there is an absence of antibody, and it presents earlier.
- The most common primary antibody deficiency (1:100-1:1000). Caused by failure of B cells to terminally differentiate into IgA-secreting plasma cells. Usually asymptomatic, but with increased infections, drug allergy, and autoimmune or atopic disease compared with controls.
- C1-C4 deficiency impairs elimination of immune complexes and apoptotic cells and is associated with autoimmune disease (e.g. SLE). C3 deficiency (or defective C3 activation) produces a similar infection spectrum to humoral immunodeficiencies, with susceptibility to pyogenic infections (e.g. S. pneumoniae). Membrane attack complex (C5-C9) deficiency has more limited effects, restricted to susceptibility to Neisseria species.
- Neisseria species; a 10,000x increased risk.
- Defects in phagocyte migration (e.g. reduced rolling adhesion from lack of sialyl-Lewis^x antigen, or defective tight adherence from leukocyte integrin β2 subunit deficiency) and defects in bacterial killing (e.g. chronic granulomatous disease, from defective ROS production).
- A defect in ROS production, due to deficiency in G6PDH, NADPH oxidase, or myeloperoxidase. Phagocytes cannot kill ingested bacteria, leading to granuloma formation, with high susceptibility to bacterial and fungal infections.
- No cell-mediated immune responses and no T cell-dependent antibody responses, leading to severe opportunistic infections; infants normally die in the first year of life unless given IVIG and bone marrow transplantation.
- Malnutrition, malignancy/myelodysplasia, iatrogenic causes (splenectomy, prosthetic implants), infection (e.g. HIV/AIDS, measles, post-sepsis), cytotoxic drugs, and immunosuppressive drugs.
- Inhibition of T cell activation, inhibition of lymphocyte proliferation, lymphocyte depletion, and inhibition of specific cytokines/cytokine receptors.
- Signal 1: T cell receptor-MHC interaction. Signal 2: co-stimulation (CD28-CD80/86, CD154-CD40). Signal 3: cytokines (e.g. IL-12). T cell proliferation itself is IL-2 dependent.
- Calcineurin inhibitors (cyclosporine, tacrolimus) block the NFAT signalling pathway and block IL-2 production, with minimal effect on B cells or myeloid cells. CTLA-4 fusion proteins (belatacept, abatacept) inhibit the co-stimulatory interaction between CD80/86 and CD28.
- Corticosteroids inhibit transcription factors AP-1 and NFκB, reducing IL-2 and other cytokine expression (among other effects). mTOR inhibitors (sirolimus, everolimus) block IL-2 signalling. Azathioprine, a purine analogue, inhibits purine synthesis needed for nucleic acid synthesis.
- Common variable immunodeficiency (CVID) is most likely. Unlike Bruton’s agammaglobulinaemia (where B cell maturation is arrested at the pre-B cell stage and antibody is absent), in CVID B cell numbers are normal but the cells are functionally deficient due to a block in maturation/differentiation, and it is typically less severe, often presenting in adulthood.