T2-L4: Immunodeficiency Flashcards
Define immunodeficiency.
Immunodeficiency - Clinical situations where the immune system is not effective enough to protect the body against infection. This can be:
- Primary - inherit defect within the immune system. This is usually genetic and presents at childhood. - Secondary - Immune system affected due to external causes, these are more common.
List the main types of primary immunodeficiency.
- T cell defects
- B cell defects
- Complement deficiency
- Phagosome defect
- Antibody deficiency
Give examples of causes of secondary immunodeficiency.
- Drugs e.g. methotrexate used in the treatment of Rx. Other examples include adti-convoluscents, myleosuppressives and steroids.
- Infection e.g. HIV and TB
- Malignancy e.g. lymphoproliferative disease, myeloma
- Protein Loss e.g. through burns, scarring, malnutrition, enteropathy as this leads to antibodies deficiency
- Breakdown in physical barriers e.g. cystic fibrosis the mucosal barrier of the lungs is broken down due to recurrent infection
Give an example of a pathogen recognition receptor.
TLR - These recognises PAMPs (pathogen associated molecular pattern) such as Lipopolysaccharide. TLR4 recognise lipolysaccaride and TLR5 recognises Flagellin.
Other examples include NLRs and RLHs.
How does IRAK4 deficiency present? How is it treated?
MyD88 and IRAK4 are involved in the cascade leading to the production of inflammatory cytokines.
- Leads to recurrent infection especially streptococcus and staphylococcus like pneumonia, meningitis and arthritis
- Normal levels of immunoglobulins, normal lymphocytes and neutrophils
- CRP may only be marginally raised in the infection
- Poor inflammatory response
- Susceptibility to infection decreases with age
Treatment is prophylactic antibiotics and IV immunoglobulins is severe.
There is no downstream signalling after the phagocyte has recognised the bacteria. This is not much of an inflammatory response. Typically these children have a pneumonia but no fever.
What is the role of gp91phox? How can a deficiency affect a patient?
Contained in the NADPH complex on the membrane of the lysosome.
NADPH releases an electron which binds to oxygen leading to a superoxide leading to hypochlorous acid (bleach). This kills the bacteria or fungi which has been engulfed. Chronic granulomatous disease is a disease of the NADPH complex - abnormality of gp91fox. Since encoded on the X chromosomes it typically affects males and females are carriers. They typically present with granulomas - collection of macrophages which go to the site of infection try and engulf it but cannot destroy it. Present with:
- Recurrent abscesses: lung, liver, bone, skin, gut
- Unusual organism infections e.g. Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi
- Rx: haemopoeitic stem cell transplant (as they usually succumb to infection), antibiotics (treated with this up to the point fo a bone marrow transplant).
What is the likely diagnosis of the following case:
- Recurrent abscesses: lung, liver, bone, skin, gut
- Unusual organisms e.g.
- Staphylococcus, Klebsiella, Serretia, Aspergillus, Fungi
- Rx: haemopoeitic stem cell transplant, antibiotics
Chronic granulomatous disease
- Chronic granulomatous disease is a disease of the NADPH complex - abnormality of gp91fox. Since encoded on the X chromosomes it typically affects males and females are carriers. They typically present with granulomas - collection of macrophages which go to the site of infection try and engulf it but cannot destroy it.
How do we test for chronic granulomatous disease?
- Neutrophil Function Test.
• Tests rely on a reduction (gain of electron) on neutrophil function test - as an electron is released
Measure Dihydrorhodamine in neutrophils reduction using flow. We stimulate the neutrophil with PMA - the proportion of reduced DHR goes up. In the patient with X-linked CPG the cells are unable to reduce DHR. - Nitro blue tetrazolium dye reduction
What complement proteins are deficient in SLE, infections and myositis?
C2 and C4
What does C5-9 deficiency present with?
Recurrent bacterial meningitis particularly Niesseria meningitis.
What is the role of antibodies?
- Agglutination
- Neutralisation
- Precipitations of dissolved antigens
- Activation of complement leading to the lysis of cells
What is the likely diagnosis of the following case:
- Male patient
- Presented before the age of 5
- 3 hospital admissions from pneumonia
- Recurrent chest infections in between
Sinusitis - Mothers brother passed away aged 35 from bronchiectasis
Bloods:
- No B cells, normal T cells
- No IgG, IgA, IgM
- CT: bronchial thickening, evidence of recent pneumonia
X-Linked Agammaglobulinaemia.
No IgG, IgA and IgM.
It is due to a defect in Bruton’s Tyrosine Kinase - BTK is also called AGA.
BTK is downstream molecule of the B cell receptor. BTK is encoded on the X-chromosome. When B cells are maturing, at the stage when they are expressed, the B cells do not mature past this.
Give examples of B cell defects.
- CVD
- IgA deficiency - the most common deficiency. Slightly increased risk of infection, but some can progress to CVID
- X-linked hyper IgM syndrome
- Transient hypogammaglobineamia of infancy - a child is born with maternal IgG. In the first 6 months they start making there own but there can be a slight lag in this.
What is the result of defects in B cells?
- Loss of antibody secretion.
- Usually leads to recurrent bacterial infection with pyogenic organisms e.g. haemophilus and Neisseria
- Treat with antibiotics then i.v IgG for life.
- Most are very serious
- Some less serious e.g. IgA deficiency.
• 1 in 5-700
• Some completely well
• Higher risk of autoimmune diseases e.g. coeliac
What is the likely diagnosis of the following case:
- 50 year old female
- History of rheumatoid arthritis- severe
- No infections most of adult life, but two year history of recurrent bacterial chest infections - 5 courses of antibiotics over the winter period
PMH: asthma - Drug Hx: currently on methotrexate and infliximab, previously rounds on Rituximab. Has also had gold, sulfasalazine in the past
- Ix: slightly low B and T cells, low IgG and IgA
Secondary antibody deficiency due to drugs. This is comparatively common.
Rituximab targets CD20 on the B cells and eliminates them from the immune system. They will repopulate leading to lower levels of B cells. Other drugs such as methotrexate will affect other parts of B cells.
Treatment is:
- Long term antibiotics to prevent infection
- May require prolonged courses in the case of infection as they do not have there own antibodies
- Immunoglobulin G replacement therapy (most potent and useful in clearing infection)
