Immune System

IMMUNE DEFICIENCY

Immune deficiency may arise through intrinsic defects in immune function, but is much more commonly due to secondary causes including infection, drug therapy, malignancy and ageing.
The consequences of deficiencies of the immune system include recurrent infections, autoimmunity and susceptibility to malignancy.
severe infections or infections caused by unusual organisms or at unusual sites are the most useful indicator
Immune def : 1ry or 2ry

Warning signs of immune deficiency

≥ 8 ear infections within 1 year
≥ 2 serious sinus infections within 1 year
≥ 2 months on antibiotics with little effect
≥ 2 pneumonias within 1 year
Failure of an infant to gain weight or grow normally
Recurrent deep skin or organ abscesses
Persistent thrush in mouth or elsewhere on skin after infancy
Need for intravenous antibiotics to clear infections
≥ 2 deep-seated infections such as sepsis, meningitis or cellulitis
A family history of primary immune deficiency


Primary phagocyte deficiencies
usually present with recurrent bacterial and fungal infections which may affect unusual sites
Leucocyte adhesion deficiencies These are disorders of phagocyte migration, They are characterised by recurrent bacterial infections but sites of infection lack pus or neutrophil infiltration.
Chronic granulomatous disease: mutations in the genes encoding the NADPH oxidase enzymes, which results in failure of oxidative killing. The defect leads to susceptibility to catalase-positive organisms such as Staphylococcus aureus, Burkholderia cenocepacia and aspergillus. Intracellular killing of mycobacteria in macrophages is also impaired. Infections most commonly involve the lungs, lymph nodes, soft tissues, bone, skin and urinary tract, and are characterised histologically by granuloma formation.

Defects in cytokines and cytokine receptors : Defects of cytokines such as IFN-γ, IL-12 or their receptors also result in failure of intracellular killing, and individuals are particularly susceptible to mycobacterial infections. Detailed assessment of cytokine deficiencies is currently only performed in specialised laboratories.

Complement pathway deficiencies

can present with recurrent infection with encapsulated bacteria, particularly Neisseria species.
genetic deficiencies of the classical complement pathway (C1, C2 and C4) are associated with a high prevalence of autoimmune disease, particularly systemic lupus erythematosus
Deficiency of the regulatory protein C1 esterase inhibitor is not associated with recurrent infections but causes recurrent angioedema
Patients should be vaccinated with meningococcal, pneumococcal and H. influenzae B vaccines in order to boost their adaptive immune responses. Life-long prophylactic penicillin to prevent meningococcal infection is also recommended. At-risk family members should be screened for complement deficiencies with functional complement assays.

1ry deficiencies of the adaptive immune system

Primary T-lymphocyte deficiencies
These are characterised by recurrent viral, protozoal and fungal infections. In addition, many T-cell deficiencies are associated with defective antibody production because of the importance of T cells in providing help for B cells
Di George syndrome: defect of the 3rd/4th pharyngeal pouch
Bare lymphocyte syndromes : absent expression of HLA molecules within the thymus
Autoimmune lymphoproliferative syndrome: failure of apoptosis of lymphocytes
The principal tests for T-lymphocyte deficiencies are a total lymphocyte count and quantitation of lymphocyte subpopulations by flow cytometry, HIV test
Patients should receive anti-Pneumocystis and antifungal prophylaxis, and require aggressive management of specific infections


Combined B- and T-lymphocyte immune deficiencies:
is caused by defects in lymphoid precursors and results in the combined failure of B- and T-cell maturation.
The absence of an effective adaptive immune response causes recurrent bacterial, fungal and viral infections soon after birth.
Bone marrow transplantation is the only current treatment option, although specific gene therapy is under investigation.

Primary antibody deficiencies:

characterised by recurrent bacterial infections, particularly of the respiratory and gastrointestinal tract. The most common causative organisms are bacteria such as Strep. pneumoniae and H. influenzae. These disorders may present in infancy, when the protective benefit of transferred maternal immunoglobulin has waned
Selective IgA deficiency
Common variable immune deficiency
Specific antibody deficiency or functional IgG antibody deficiency
Serum immunoglobulins should be measured
specific antibody responses to known pathogens should be assessed

Management:

All patients with antibody deficiencies require aggressive treatment of infections and prophylactic antibiotics may be indicated.
The mainstay of treatment is immunoglobulin replacement (intravenous immunoglobulin, IVIgG), which is derived from pooled plasma and contains IgG antibodies to a wide variety of common organisms. IVIgG is usually administered every 3-4 weeks with the aim of maintaining trough IgG levels within the normal adult range. Treatment may be self-administered and is life-long.
With the exception of selective IgA deficiency, immunisation is generally not effective because of the defect in IgG antibody production. As with all primary immune deficiencies, live vaccines should be avoided

Secondary immune deficiencies

Physiological
Ageing
Prematurity
Pregnancy
Infection
HIV
Measles
Mycobacterial infection
Iatrogenic
Immunosuppressive therapy
Antineoplastic agents
Corticosteroids
Stem cell transplantation
Radiation injury
Anti-epileptic agents


Malignancy
B-cell malignancies including leukaemia, lymphoma and myeloma
Solid tumours
Thymoma
Biochemical and nutritional disorders
Malnutrition
Renal insufficiency/dialysis
Diabetes mellitus
Specific mineral deficiencies, e.g. iron, zinc
Other conditions
Burns
Asplenia/hyposplenism