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Terms in this set (84)
Secondary Immunodeficiency disorder
Partial or full impairment of the immune system which leaves patients unable to resolve infections.
Primary immunodeficiency Disorders (PIDs)
= congenital single gene defect.
- Usually inherited.
- Manifests in early age, diagnosed in childhood.
- Potentially life threatening
- >300 forms but very rare.
- More common in males= X linked conditions.
- Provide invaluable research into immune function
- Antibody disorders= most common.
Secondary immunodeficiency disorders (SIDs)
as a result of disease or environmental factors.
- More common
- Manifests at any age
- Treatment of primary condition can lead to resolution of immunodeficiency.
Causes of secondary immunodeficiency Disorders
- Malnutrition= biggest global cause (protein deficiency causes decrease in T cell function).
- Drug effects= chemotherapy, immunosuppressant drugs.
Chronic infections- Most common: HIV/AIDS
Malignancy= leukaemia, lymphoma and myeloma.
Other: Radiotherapy, extreme age (very young or old & unwell).
Clinical Features of immunodeficiencies
- Increased frequency, severity and duration of infection.
- Unexpected complications/unusual manifestations of infection
- Infections with organisms normally considered low pathogenicity.
- Non-infectious manifestations in GI, endocrinological and haematological organ systems e.g. inflammatory or autoimmune conditions.
evere= requires hospitalisation or IV antibiotics
ersistent= won't completely clear up or happens very slowly.
nusual= caused by an uncommon organism
uns in family (Primary)
Clinical findings of immunodeficiencies
Frequent Ear infections
Frequent Sinus infections
2 or more months on antibiotics.
Failure to thrive
Frequent deep-seated infections including septicaemia.
Skin lesions, eczema
Frequency of ear infections
4 or more in 1 year
Frequency of sinus infections, pneumonia and deep seated infections
2 or more in 1 year
Take history, physical exam and baseline blood tests.
Diagnostic testing: complete blood count, immunoglobulin levels (rule out SCID, AIDs).
B cell maturation
Predisposition to specific infections is determined by
The component of the immune system that is defective
- Most common PID.
- Antibody deficits commonly result in bacterial infections causing Otitis, pneumonia and Sinusitis, GI disturbances and autoimmunity.
- Infectious organisms include:
Pneumococcus & H. influenzae
- Lab studies: low immunoglobulins +/- B cell abnormalities.
- Untreated patients can develop bronchiectasis
- Cornerstone therapy= immunoglobulin replacement therapy (IgG)
Examples of Primary Antibody immunodeficiencies
Transient physiological agammagloulinaemia of neonate
X-linked agammaglobulinaemia of Bruton (Bruton's disease)
Common variable hypogammaglobulinaemia (CVID)
Selective IgA deficiency.
Examples of Secondary antibody deficiencies
Chronic lymphocytIc leukaemia (CLL)
Transient physiological agammaglobulinaemia of the neonate
Primary antibody deficiency.
- Characterized by decreased serum IgG with or without decreased immunoglobulin A (IgA) and immunoglobulin M (IgM) levels less than 2 standard deviations (SDs) from age-adjusted reference range levels in infants older than 6 months of age in the first years of life but with normal to near-normal antibody responses to protein immunisations.
= Newborn as transition period of low IgG levels which should resolve but doesn't
Bruton's disease (X-linked agammaglobulinemia)
- Primary antibody deficiency.
- characterised by the absence of mature B cells, resulting in severe antibody deficiency and recurrent infections. It can manifest in an infant as soon as the protective effect of maternal immunoglobulins wanes at around six months of age.
-Recurrent otitis media is the most common type of infection seen before diagnosis
-caused by mutations in the BTK gene.
Common Variable Hypogammaglobulinemia (CVID)
- Primary antibody
Characterised by recurrent infections and low antibody levels, specifically in immunoglobulin (Ig) types IgG, IgM and IgA.
Genetic cause not fully understood.
Majority of cases, the diagnosis is not made until the third to fourth decade of life. Permanent damage to the respiratory tract (bronchiectasis) may occur due to severe and repeated infections.
Example of secondary antibody deficiencies
- Chronic Lymphocytic Leukaemia (CLL)
- Multiple Myeloma
Selective IgA deficiency
Characterised by undetectable IgA levels in the blood and secretions but no other Ig or immune deficiencies.
Affects 1 in 400-1000
Unknown genetic cause
IgA works to protect body surfaces that come into contact with outside organisms, such as the respiratory tract and gut, so if someone has infections, these are the most common sites of infection
Clinical features of Selective IgA deficiency
1. Asymptomatic (majority)
2. Recurrent infections of mucosal surfaces (50%)
Diagnosing Selective IgA
- Blood IgA
- Other Ig levels normal.
- Normal B & T cell number and function.
No specific treatment., treat symptoms and complications.
Infections as a result of Antibody immunodeficiencies
e.g. Streptococcus pneumoniae & Haemophilus influenzae
- Most common SID.
- Commonly result in recurrent viral, fungal, protozoal and intracellular bacterial infections causing:
= Deep-seated infections,
P. jirovecii Pneumonia
= Reactivation of latent viral infections
- Children can be killed by opportunistic infections or live vaccines.
- Lab studies: lymphocyte subpopulation and proliferation tests.
Haematopoietic stem cell transplantation
Gene therapy being trialled.
Lymphocyte proliferation test
Tests how well lymphocytes respond to growth factors.
Examples of primary lymphocyte deficiencies
DiGeorge syndrome (Thymic hypoplasia)
Severe combined immunodeficiency (SCID)
DiGeorge Syndrome (Thymic Hypoplasia)
caused by the deletion of a small segment of chromosome 22.
Intrauterine damage to the third and fourth pharyngeal pouches results in failure of development of the thyroid and parathyroid glands. This results in a decrease in the number and function of T cells. Clinical features include abnormal facies, cardiac defects, hypoparathyroidism and recurrent infections.
Affects maturation of T cells
Symptoms can be variable, they often include congenital heart problems, specific facial features, frequent infections, developmental delay, learning problems and cleft palate
Rare X-linked recessive disease characterised by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhoea (secondary to the thrombocytopenia).
Defect in WAS gene leads to abnormal WAS protein-which activates actin polymerisation and has been shown to affect the immune synapse (interface between antigen-presenting 'target' cell and T cell).
Abnormally low levels of thrombocytes, also known as platelets, in the blood.
A normal human platelet count ranges from 150,000 to 450,000 platelets per microlitre of blood.These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia requiring emergency treatment is a platelet count below 50,000 per microlitre.
Examples of secondary lymphocyte deficiencies
- Malnutrition= thymus atrophic: normally implicated in the production and maintenance of T cell immunity - T cell no. reduced
- Hodgkin's lymphoma= causes T cell deficiency & depletes T cell in lymphoid tissue
-Infections: Measles, Malaria, Leprosy and HIV. = all impair T cell function -sometimes leading to impaired B cell function too e.g. with malaria and HIV
- Drugs: glucocorticoids and cytotoxic chemotherapy.
Severe Combined Immunodeficiency (SCID)
- Rare but potentially fatal disorder.
- Severe deficits in cellular and humoral immunity.
- Diverse genetic causes
- More common in Men (4:1) (common gamma chain deficiency is X linked).
- Classified by inheritance pattern & lymphocytes present.
- Untreated= will kill child by 1.
Types of SCID
- Common gamma chain deficiency (most common).
- Adenosine deaminase (ADA) deficiency.
-JAK3 kinase deficiency
- MHC class II deficiency
- Recombinase activating gene (RAG) deficiency
MHC I vs II
MHC I glycoproteins found on all nucleated cells.
MHC II only on APCs.
Common gamma chain deficiency
- 40% positive family history.
- Gene encodes common gamma chain (receptor)
- 60% of SCID cases
Absence of T cell and NK cells but still have B cells
Test: gc protein lvels and gc gene mutation
Adenosine deaminase (ADA) deficiency
- Autosomal recessive.
- ADA= widely expressed enzyme
involved in purine metabolism
- Get build up of toxic metabolic products:
abnormal immune cell development and Non-immune symptoms e.g. deafness
- 15% of SCID cases
- *Absence of T, NK and B cells
Immediate treatment: PEG-ADA (artificial ADA).
SCID clinical features
- Usually less than 3-6 months old.
- Severe & life-threatening infections.
- Opportunistic infections.
- Infections from 'live' vaccines.
- Failure to thrive.
- Chronic diarrhoea and thrush
- Decreased T cell count
- Poor proliferation of mitogens
- Variable number of B cells
- Low immunoglobulins
Further blood tests & genetic testing needed to diagnose
chemical substance that encourages a cell to commence cell division, triggering mitosis
Immediate treatment of SCID
Isolation until definitive treatment,
- Prophylactic medication
- Immunoglobulin therapy.
- Blood transfusion
- Cytomegalovirus (CMV) testing.
- Avoid live vaccinations e.g. MMR
Definitive treatment of SCID
Haematopoietic stem cell transplantation
Lymphocyte immunodeficiency common infections and symptoms
Viruses e.g. Herpes simplex & rotavirus
Fungi e.g. Pneumocystis jirovecii, Protozoa & intracellular bacteria e.g. Mycobacteria .
Deep seated infection, Thrush, Pneumonia & Reactivation of latent viruses
Commonly result in predominantly bacterial infections that occur at interface between host and environment.
, pneumonia, deep-seated infections, GI tract disturbances, granulomatous inflammation.
Lab studies: granulocyte function tests.
Granulocyte-colony stimulating factor or stem cell transplant
Nodular collection of epithelioid macrophages surrounded by a rim of lymphocytes that surrounds pathogen.
Examples of Primary Phagocyte deficiencies
- Leucocyte adhesion deficiency (LAD)
- Chronic granulomatous disease (CGD)
Examples of Secondary Phagocyte deficiencies
Drugs: corticosteroids and cytotoxic chemotherapy.
Reduced production or accelerated removal of granulocytes.
Leucocyte adhesion deficiency (LAD)
Failure to mobilise WBCs to tissue.
Chronic Granulomatous Disease (CGD)
Failure to kill infectious organisms.
Chronic inflammation of gums etc.
Neutrophils can't produce chemicals used to kill pathogens.
Missing a vital protein in an enzyme called NADPH oxidase
Phagocyte Immunodeficiency infections
Predominantly bacteria e.g. Staphylococcus aureus (pyogenic) & Pseudomonas, and Fungi e.g. Aspergillus
Symptoms of Phagocyte immunodeficiency
Abscesses, Deep seated infection, Pneumonia, GI tract disturbances & Granulomatous inflammation
- Protein in complement system is absent or malfunctioning.
- Rare= redundancy between components of the immune system so not always diagnosed
Commonly result in:
- Recurrent and/or serious bacterial infections (often pyogenic e.g. streptococci & Hib may lead to sepsis)
No specific treatments
Lab studies for complement immunodeficiencies
Total complement activity test (
Specific complement activity test (
) = measures alternative pathway activity.
Antibody deficiencies commonly result in:
in extracellular bacterial infections whereas T cell deficiencies result in intracellular infections e.g. by viruses
chlamydia, listeria, legionella, nocardia, neisseria menigitidis, rickettsia, mycobacterium, salmonella typhi.
Much smaller than other bacteria, can only grow inside other cells
Sinusitis caused by bacterial infection
Common in Ab ID disorders
Main effect of antibody deficit
- Inability to clear extracellular polysaccharide encapsulated pyogenic bacteria
- no Ab opsonisation of bacteria for phagocytosis... recurrent ear infections and upper respiratory tract infections leading to pneumonia and sinus infections, diarrhoea and malabsorption, e.g. arthritis, cytopenias (antibodies attack immune cells) and lupus
Respiratory problems are commonly caused by streptococcus pneumonia & haemophilus influenza
and/or deficient specific antibody production. Abnormalities in the cells responsible for generating or maintaining an antibody response
bronchiectasis (irreversible lung infections
Chronic Lymphocytic Leukemia (CLL)
abnormal numbers of relatively mature lymphocytes predominant in the marrow, lymph nodes, and spleen.
Affects the ability of B-cells to differentiate into plasma cells leading to Ab deficiency
found in highest quantities - primarily responsible for fighting infections inside our body tissues, organs and blood with IgM
next most abundant Ig - found in blood but most commonly found in mucosal secretions E.g. tears, saliva, colostrum, genital, respiratory and gastrointestinal secretions where it can protect from infections - so called secretory IgA - exists as a dimer (small quantities of IgG and IgM also found)
Diagnosing Selective IgA deficiency
a blood test showing low IgA levels <0.5-0.7 mg/L (normal levels: 0.8-3 mg/L) - may also look at full blood count, measurement of lung function and urinalysis + thyroid function, kidney function, nutrient absorption in GI tract and autoantibodies.
Classical pathway immunodeficiency
clears immune complexes and dying cells - inability to do this can result in immune complex disease causing e.g. lupus and rheumatoid arthritis - lupus can also cause complement SID
Convergence point for the classical, alternative and lectin pathways and start of complement cascade - similar to Ab deficit - inability to clear extracellular polysaccharide encapsulated pyogenic bacteria - no complement opsonisation of bacteria for phagocytosis
Part of the terminal pathway and factor D and properdin from alternative pathway - cause meningitis and sepsis - patients can be vaccinated against this. Properdin deficiency is x-linked, all others autosomal recessive
C1 inhibitor deficiency (Hereditary angiodema)
over-activation of complement system - treated with C1 inhibitor concentrate
Secondary cause of complement deficiency.
Monoclonal antibody used to treat blood diseases
3 complement pathways
classical, alternative, lectin.
Feed into complement cascade (triggered by C3 convertase)
activated by antibodies bound to antigen.
Failure: Immune complex disease e.g. lupus (which can cause a secondary complement deficiency).
Activated by carbohydrates on pathogen surface
Activated by pathogen surface
Deficits in alternative pathway or C3 cause
similar problems to antibody deficit.
= No opsinisation
Infection with pyogenic bacteria and Neisseria spp.
Cause under-activation of complement system
Examples of Secondary complement deficiency
Complement immunodeficiency infections
Bacteria e.g. Streptococcus pneumoniae & Haemophilus influenzae (pyogenic) & Neisseria
Symptoms of complement immunodeficiency
Recurring infection, Angioedema & Autoimmune disorders
Lab studies for complement immunodeficiency
CH50 & AH50
Impact leukocyte traffic and leukocyte functions
Decrease circulating CD4+ T-cells by sequestering T-cells into lymphoid compartments
impairs T cell IL-2 production, used in transplant patients.
Can cause secondary immunodeficiency.
Deficiency of C5, C6, C7, C8, factor D and properdin
Increased susceptibility to Neisseria infections
C3 deficiency common infection
Prone to recurrent pyogenic infections
Extracellular encapsulated bacteria that cause the formation of pus at sites of infection.
e.g. Staph Aureus,
Salmonella typhi (Bacillus typhosus)(cause of typhoid).
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