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SEM 4: Immunology > Immunodeficiencies > Flashcards

Immunodeficiencies Flashcards

1
Q

What are primary immunodeficiencies?

A
  • Primary (congenital): born with a defect in the immune system/the deficiency is in the immune cells themselves
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2
Q

What are secondary immunodeficiencies?

A
  • Secondary (acquired): caused by another diseases such as in HIV.
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3
Q

What are the clinical features of immunodeficiency?

A
  • Recurrent infections
  • Severe infections with unusual pathogens such as Aspergillus, pneumocystis
  • Also at unusual sites such as lower abscess and osteomyelitis
  • This all also depends on the age of the patient
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4
Q

What are the warning signs of primary immunodeficiency (PID)?

A

2 or more must be present:

  • 8 or more new ear infections within 1 year
  • 2 or more serious sinus infection within 1 year
  • 2 or more months on antibiotics with litter effect
  • 2 ore more pneumonias within 1 year
  • Failure of an infant to gain weight or grow normally.
  • Recurrent deep skin or organ abscesses
  • Persistent thrush after the age of 1
  • Need for intravenous antibiotics to clear the infection
  • 2 or more deep-seated infections
  • A family history of primary immunodeficiency
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5
Q

What usually causes PID?

A

It is usually due to genetic mutations which will lead to abnormallity in the immune system. They are infrequent but can be life-threatening.

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6
Q

Which parts of the body systems can the PID affect?

A

It can affect the adaptive immune system such as T and B cells, or can affect the innate immune system such as phagocytes and complement.

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7
Q

Where do the majority of PID occur?

A
  • About 50% of PID are in antibodies
  • About 30% in T cells
  • About 18% in phagocytes
  • About 2% in complement
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8
Q

What are the defects that can oocur in the adaptive immunity?

A
  • Can have B cells only defects
  • Can have T cells only defects
  • Can have combined defects of both
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9
Q

What do B cell defects lead to?

A

They will lead to impaired antibody production

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10
Q

What do T cell defects lead to?

A

Also lead to impaired antibody production because for B cells to undergo the class switch of antibody, they need certain cytokines from T cells.

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11
Q

When can defects in the T cell or B cell occur?

A

They can be early during development or later on during activation.

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12
Q

What are the major B lymphocyte disorders?

A
  • X-linked agammaglobulinemia or Bruton’s disease (most important)
  • Common variable immunodeficiency (CVID)
  • Selective IgA deficiency
  • IgG2 subclass deficiency
  • Specific Ig deficiency with normal Igs.
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13
Q

What is an example of a combined immunodeficiencies?

A

Severe combined immunodeficiency (SCID)

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14
Q

What are predominant T cell disorders?

A
  • DiGeorge syndrome
  • Wiskott-Aldrich syndrome
  • Ataxia-Telangiectasia
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15
Q

What is X-linked Agammaglobulinemia?

A

It is the major B cell disorder that was first described immunodeficiency

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16
Q

What causes X-linked Agammaglobulinemia?

A

There is a deficiency in the BTK gene in the X chromosome. Therefore, when not present, leads to block in B cell development at pre-B stage. This means there is no production of antibodies.

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17
Q

What is the BTK gene?

A

This is a gene that encodes for Burton’s tyrosine kinase. This enzyme is needed for pre-B cell receptor signalling.

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18
Q

How does X-linked Agammaglobulinemia present symptoms?

A
  • The patient suffers from severe bacterial infection. - Symptoms appear during the 2nd half of the first year, and they usually manifest in the lungs, ears and GI tract.
  • Some patients also develop auto-immune diseases
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19
Q

Why do X-linked Agammaglobulinemia symptoms present in the 2nd half of the first year?

A

The reason it appears during the second half of the first is because during pregnancy antibodies form the mother (IgG) can cross to the foetus and during breastfeeding antibodies (IgA) can cross the baby.

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20
Q

What are the white cell counts for X-linked Agammaglobulinemia investigated in the lab?

A
  • B cell count will be none or reduced depending on the severity of the defect
  • Igs count will be none or reduced depending on the severity of the defect
  • T cells and T cell mediated responses will be normal.
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21
Q

How is X-linked Agammaglobulinemia treated?

A
  • Ig replacement therapy
  • Can be given as IVIg at 2-3 week intervals
  • Can also be given subcutaneous Ig weekly
  • Prompt antibiotic therapy
  • Not given live vaccines
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22
Q

What does SCID: combined immunodeficiency involve?

A

It involves both T and B cells, and is a syndrome not a disease, because has multiple causes but the result will always be a reduced number of B and T cell count.

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23
Q

How do the symptoms of SCID present?

A

Patient presents well at birth; problems arise after the 1st month.
Symptoms include diarrhoea, weight loss , persistent candidiasis
They express severe bacterial and viral infections.
If given live vaccine, they will not be able to clear the vaccine and will develop the disease
Unusual infections such as pneumocystis and CMV

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24
Q

What causes SCID?

A
  • Common cytokine receptor y-chain defect
  • RAG-1/RAG-1 defect
  • Adenosine deaminase deficiency (ADA)
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25
Q

How does the common cytokine receptor y-chain defect cause SCID?

A
  1. This is a signal transducing component of receptors for a number of cytokines including IL7 and IL15.
  2. Therefore, in absence of this, there is defective T cell development and therefore eventually also lack in B cell and low antibodies.
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26
Q

What is IL7 and IL15 needed for?

A

IL7 is needed for survival of T cell precursors

IL15 is needed for NK survival.

27
Q

What is RAG-1 and what does a defect cause?

A

These genes are needed for normal T cell and B cell antigen receptors. Therefore, is these genes are mutated then T cells and B cells will not contain antigen receptors and therefore will not develop and mature.

28
Q

What is adenosine deaminase needed for?

A

It is an enzyme that is important for cells tha proliferate very rapidly and therefore accumulate a lot of deoxyadenosine and deoxy-ATP which are toxic if deficient.

29
Q

What are the lab investigations shown by SCID?

A
  • Full blood count, which will show low total lymphocyte count.
  • Pattern should show, low T cell, low B cell and sometimes low NK (due to low IL15)
  • Low Igs
  • T cell function will be down and therefore low proliferation and low production of cytokines
30
Q

What is the treatment of SCID?

A
  • Isolation to prevent further infections
  • Not given live vaccines
  • Not give blood products from CMM positive donors
  • IVIg replacement
  • Treat infections with antibiotics
  • Bone marrow/haemtopoietic stem cell transplant
  • Gene therapy for ADA and y-chain genes
31
Q

What is the outcomes of someone with SCID?

A

Dependent on the promptness of diagnosis:

  • When there is early diagnosis, good donor match and no infections; pre-transplant is more than 80% survival chance
  • When there is late diagnosis, chronic infection and poorly matches donors; there is less than 40% survival chance
  • Regular monitoring post Bone marrow transplant
32
Q

What is DiGeorge syndrome?

A

It is a predominant T cell disorder as due to thymic hypoplasia and therefore, the T cells cannot develop.

33
Q

What causes DiGeorge syndrome?

A

It is a syndrome due to a mutation which affects the T cell development but also affects the development of multiple organs and the failure of development of organs that arise from the 3+4th pharyngeal pouches (one of them being the thymus).

34
Q

What are the symptoms of DiGeorge Syndrome?

A
  • Complex array of development defects
  • Dysmorphic face: Cleft palate, low set ears and fish-shaped mouth
  • Hypocalcaemia and cardiac abnormalities
  • Variable immunodeficiency due to absent/reduces thymus leading to abnormal T cell development
35
Q

What is Wiskott-Aldrich syndrome (WAS)?

A

It is an X-linked syndrome that is due to defects in the WASP protein.

36
Q

What is WASP?

A

It is a protein that is involved in actin polymerisation. Therefore, defects in this leads to defects in signalling.

37
Q

Why is WAS a syndrome and not a disease?

A
  • There are defects in other areas such as defects in platelets.
    They develop thrombocytopaenia, eczema and infections.
  • They have progressive immunodeficiency (T-cell loss), due to less signalling and therefore, T cell count goes down and T cell proliferation goes down.
  • Antibody prodcution also decreases leading to low IgM, IgG and high levels of IgE. IgE contributes to the presence of eczema.
38
Q

What is Ataxia-Telangiectasia?

A

An autosomal recessive disease. There are defects in the cell cycle checkpoint gene (ATM).

39
Q

What is ATM?

A
  • ATM genes are important as a sensory of DNA damage. If DNA damage is detected, p53 is activated. Therefore, apoptosis of cells with damaged DNA is triggered. However, if there is a defect in this gene, this won’t occur.
  • ATM is also important for gene stablisation of DNA double strand break complexes during V(D)J recombination. Therefore, this is not present when ATM is defected leading to defect in generation of lymphocyte antigen receptors and lymphocyte development.
40
Q

What are the symptoms of Ataxia Telangiectasia?

A
  • Progressive cerebellar ataxia
  • Typical telangiectasia
  • Immunodeficiency: combined immunodeficiency in both B and T cell; defects in production of switched antibodies; T cell defects; upper and lower respiratory tract infection and autoimmune phenomena, cancer.
  • Increased incidence of tumours later in life
41
Q

What are the primary immunodeficiences in innate immunity?

A
  • Phagocyte defects: affecting a no. of cells or quality of them
  • Complement defects
42
Q

What are the diseases that are caused by phagocyte defects?

A
  • Chronic granulomatous disease
  • Chediak-Higashi syndrome
  • Leucocyte adhesion defects (LAD)
43
Q

How is chronic granulomatous disease caused?

A

Defective oxidation killing of phagocytosed microbes. Due to a mutation in phagocyte oxidase NADPH components. This means certain pathogens do not get eliminated properly by phagocytes. Therefore, the patients develop granulomas in order to try to prevent the spread of the pathogen.

44
Q

How to diagnose Chronic granulomatous disease?

A

Test measure the oxidative burst.

  • By using a NBT test which is nitroblue tetrazolium reduction.
  • By using flow cytometry assay dihydrorhodmaine
45
Q

Describe the NBT test

A
  1. Take neutrophils, stain them with nitroblue tetrazolium
  2. Then activate them by adding a microbe.
  3. Test for the production of reactive oxygens.
  4. If they generate ROS, they will produce this blue colour.
46
Q

Describe the flow cytometry assay dihydrohodmaine

A
  1. Take neutrophils from patient
  2. Activate them with microbe
  3. Measure fluorescence
47
Q

What is Chediak-Higashi syndrome?

A

It is a rare genetic disease that is due to defect in the trafficking of the lysosome which means the lysosome won’t fuse with the phagosome due to defect in the LYST gene.
This means the enzymes form the lysosome will not kill the pathogen and so the patient will suffer from severe recurrent infections.

48
Q

How are Chediak-Higashi syndrome diagnosed in the lab?

A
  • Decreased number of neutrophils shown on the blood film

- Neutrophils have giant granules because lysosomes cannot fuse with phagosome so they fuse with each other.

49
Q

What is Leucocyte adhesion defects disorder (LAD)?

A

This is not a defect in the phagocytosis pathway, instead it is due to defect in the mechanisms that allow the phagocyte to be mobilised to the site of infection.

50
Q

Where can the defects be in LAD?

A
  • Beta2 chain integrins
  • Sialyl lewis X
  • Delayed umbilical cord separation leads to defect in beta2 chain integrins
51
Q

What are the symptoms of LAD?

A
  • Skin infections

- Intestinal and perianal ulcers

52
Q

What are the investigations to identify LAD?

A
  • Low neutrophils chemotaxis

- Low integrins on phagocytes: can be detected via flow cytometry.

53
Q

How can complement deficiencies come about?

A
  • Defects can affect different complement factors
  • Predisposition to infection with different pathogens
  • Symptoms differ depending on C factor affected; therefore, help with diagnosis.
54
Q

What are the examples of complement defects?

A
  • Defect in the terminal membrane complex (MAC) which is C5-C9; they will have recurrent infections from Neisseria group pathogens.
  • Defect in C3; will have severe infections from pyogenic bacteria.
  • Defect in the classical components of complement activation such as C1, C2 and C4; they will have SLE-like syndrome.
  • Defect in the ability to switch off complement pathway, due to deficiency in C1 inhibitory, they will get hereditary angioneurotic oedema
55
Q

What is hereditary angioneurotic oedema?

A

This is acute oedema in the skin/mucosa which leads to vomiting, diarrhoea and airway obstruction.

56
Q

How to investigate complement deficiencies?

A
  • Look at complement function: CH50 haemolysis
  • Quick and easy
  • Measure individual components
57
Q

What is the treatment for complement deficiencies?

A
  • Minimise/control infections
  • Replace defective/absent component of complement
  • Immunoglobulin replacement therapy and gene therapy
58
Q

Summaries the primary immunodeficiencies treatment principles

A
  • Prompt treatment of infection
  • Prevention of infection via isolation, antibiotic prophylaxis and vaccination (but NOT LIVE VACCINATION)
  • Good nutrition
59
Q

How does secondary immunodeficiency occur?

A

These are acquired due to another disease that patient has. This could be infections, malignancy, extremes of age, nutrition, chronic renal disease, splenectomy, trauma/surgery and immunosuppressive drugs.

60
Q

Which infections can cause secondary immunodeficiency?

A
  • Viral: HIV, CMV, EBV, Measles, Influenza
  • Chronic Bacterial: TB, Leprosy
  • Chronic Parasitic: Malaria, Leishmaniasis
  • Acute Bacteria: Septicaemia
61
Q

What malignancy can cause secondary immunodeficiency?

A
  • Myeloma
  • Lymphoma
  • Leukaemia
62
Q

How can extremes of age contribute to secondary immunodeficiency?

A
  • Prematurity: Premature delivery interrupts placental transfer of IgG
  • Old age: Decline in normal immune function
63
Q

What nutrition disorders can cause secondary immunodeficiency?

A
  • Anorexia

- Iron deficiency

64
Q

How does trauma/surgery cause secondary immunodeficiency?

A
  • Burns
  • Smoking
  • Alcohol

SEM 4: Immunology (15 decks)

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