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Cellular and Molecular pathology > 24. Immunodeficiency > Flashcards

24. Immunodeficiency Flashcards

1. Understand that failures in host defence may be inherited or acquired. 2. Use appropriate examples to explain how different classes of primary immunodeficiency affect different components of the immune system. 3. List the major causes of secondary immunodeficiency and describe how immunity is compromised in these conditions.

1
Q

What does there need to be for a healthy immune response?

A

not too much immunity but enough to mount a response

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2
Q

What is a primary immunodeficiency?

A
  1. Some aspect of the host immune response is absent or deficient due to a genetic defect.
  2. This can be defects in the cells and mediators of both innate and adaptive immunity
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3
Q

What is secondary immunodeficiency?

A

An aspect of the host immune response is absent or deficient due to an external factor

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4
Q

What can cause secondary immunodeficiency?

A
  1. Infection with agents that deplete immune cells
  2. malnutrition
  3. Immunosuppressive drugs
  4. other diseases that can deplete immune cells
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5
Q

How many primary immunodeficiencies are there?

A

over 150

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6
Q

What causes primary immunodeficiency?

A

A mutation in any one of a large number of genes that are involved in the development and function of immune cells.

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7
Q

What characterises primary immunodeficiency?

A
  1. They have very variable clinical features
  2. But often have recurrent, overwhelming infections in young children
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8
Q

How are primary immunodeficiencies classified?

A

based on the underlying immunological defect

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9
Q

What is a main feature of the immune system?

A

It contains many different parts that cooperate and communicate to form a functioning system.
A deficiency in one part can have a knock on effect on other parts of the immune response

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10
Q

Primary Immunodeficiency classification: Antibody deficiencies

A

B cell problems or defects in T cells that affect the maturation of B cells

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11
Q

Primary Immunodeficiency classification: Combined immunodeficiencies

A
  1. The most severe
  2. Problems in the development and function of T cells and/or B cells
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12
Q

Primary Immunodeficiency classification: disorders of immune regulation

A
  1. Deletion of self-reactive T cell failure
  2. Problems with apoptosis
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13
Q

Primary Immunodeficiency classification: phagocytic cell disorders

A

Problems in the development and functions of granulocytes and macrophages

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14
Q

Primary Immunodeficiency classification: complement deficiencies

A

defects in functional and/or regulatory components of the complement

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15
Q

Consequences of primary immunodeficiency: antibody deficiency

A

pyogenic infections (encapsulated bacteria leading to puss formation)

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16
Q

Consequences of primary immunodeficiency: combined immunodeficiency

A

infection by bacteria, viruses and any opportunistic pathogen

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17
Q

Consequences of primary immunodeficiency: neutrophil deficiencies

A

bacterial and fungal infections

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18
Q

Consequences of primary immunodeficiency: macrophage deficiency

A

mycobacterial diseases

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19
Q

Consequences of primary immunodeficiency: TLR defects

A

Infections that are specific for the TLR affected

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20
Q

Consequences of primary immunodeficiency: complement deficiencies

A

Pyogenic infections and increased susceptibility to autoimmunity

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21
Q

What happens in B cell development?

A
  1. They develop in the bone marrow and move through defined stages.
  2. Rearrangement of Immunoglobulin genes occurs in the pre-B cell stage and is triggered by the pre-B cell receptor.
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22
Q

What is congenital agammaglobulinemia?

A
  1. Defects in the expression or signalling of the pre-B cell receptor.
  2. This causes CA which is the lack of immunoglobulin in serum.
  3. It also causes a lack of circulating B lymphocytes
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23
Q

What is the prototypic agammaglobulinemia?

A

X-linked agammaglobulinemia

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24
Q

What causes X-linked agammaglobulinemia?

A
  1. A mutation in the Bruton tyrosine kinase (BTK) gene.
  2. This results in a defective enzyme.
  3. This causes a block in B cell development from pre-B cell to immature B cell.
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25
Q

What is the result of X-linked agammaglobulinemia?

A
  1. Circulating B cells are generally absent.
  2. No IgA, IgM, IgD or IgE production.
  3. Very low IgG levels in serum.
  4. No tonsils
  5. Tiny lymph nodes.
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26
Q

Why is there often delayed diagnosis of agammaglobulinemia disorders?

A
  1. The transient presence of maternal antibodies last for around 6-9 months after birth.
  2. This delays the diagnosis as the infant is protected
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27
Q

What infections are linked to X-linked agammaglobulinema?

A
  1. Susceptibility to pyogenic infections.
  2. Enteroviral infections in the gut can cause encephalitis.
  3. The live polio vaccine may become a paralytic poliomyelitis infection.
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28
Q

How is X-linked agammaglobulinemia treated?

A

with regular infusions of pooled human IgG

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29
Q

Why do we use pooled IgG as a treatment for agammaglobulinemia?

A

Lots of different people have been exposed to lots of different infection giving a large range of antibodies for the best protection.

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30
Q

What is common variable immunodeficiency?

A
  1. A common primary immunodeficiency.
  2. Defects in final B cell maturation leading to reduced plasma cell numbers.
  3. Patients often suffer with progressive hypogammaglobulinemia.
  4. Susceptible to recurrent infection of the respiratory and GI tract
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31
Q

What is the cause of common variable immunodeficiency?

A
  1. Clinically and genetically heterogeneous.
  2. The underlying mutation/defect is often unknown.
  3. Candidate genes include CD21, CD19 and ICOS
32
Q

What is ICOS?

A

It is expressed by T cells and binds to B cells to stimulate antibody production.

33
Q

What does common variable immunodeficiency cause?

A
  1. Reduced levels of specific antibody isotypes in all patients.
  2. Usually 2-3 different isotypes are selectively affected.
  3. Normally IgG and IgA deficiencies
  4. Patients can also be prone to autoimmunity
34
Q

What is selective IgA deficiency?

A
  1. It is the most common primary immunodeficiency.
  2. Affects 1 in 600 people.
  3. IgA is undetectable in blood and secretions but no other immunoglobulin deficiencies are present.
  4. Unknown cause.
  5. Often asymptomatic.
35
Q

What can selective IgA deficiency cause?

A
  1. Recurrent infections
  2. Autoimmunity.
  3. Allergy
    Especially if the deficiency is associated with IgG2 or IgG4 defects
36
Q

What is hyper IgM syndrome?

A
  1. Defects in the B cell class switch recombination pathway.
  2. Very high IgM levels in serum.
  3. Other isotypes present in trace amounts or absent.
  4. Lack of germinal centres
37
Q

What is the most common cause of hyper-IgM syndrome?

A
  1. Defects in CD40L
  2. Activated T cells express CD40L and binds CD40 on B cells.
  3. This is a strong co-stimulatory signal for class switch recombination and affinity maturation.
38
Q

What is severe combined immunodeficiency (SCID)?

A
  1. The most serious type.
  2. Defects in T cell development.
  3. T cells play a vital role in the adaptive response to all antigens.
39
Q

What do patients with severe combined immunodeficiency lack?

A
  1. T-cell dependent antibody responses.
  2. cell mediated immunity and cytotoxic immunity
  3. Immune memory
40
Q

What does severe combined immunodeficiency cause?

A

high susceptibility to a broad range of infectious agents

41
Q

What are some genetic defects that can cause severe combined immunodeficiency?

A

Defects in:
1. Expansion of lymphoid progenitors.
2. Pre-T cell receptor signalling.
3. Thymocyte survival
4. TCR gene rearrangements

42
Q

What are the different types of severe combined immunodeficiency?

A
  1. T cell negative, B cell positive
  2. T cell negative, B cell negative
  3. Both of these have NK cell positive and negative forms.
    eg. X-linked SCID = T- B+ NK-
43
Q

What are some characteristics of severe combined immunodeficiency?

A
  1. Thymus is very small.
  2. Many children lack lymph nodes.
  3. Even if B cells are present their function is impaired due to lack of T cell help
44
Q

What is DiGeorge anomaly?

A
  1. A defect in thymus embryogenesis.
  2. Varying levels of T cell deficiency
  3. <1% of patients develop SCID
  4. Can be treated with a thymus transplant.
45
Q

What causes DiGeorge anomly?

A
  1. A defect in the differentiation of the 3rd and 4th pharyngeal pouch.
  2. All tissues derived from these are including the thymus are effected
46
Q

What are some examples of primary defects of immune regulation?

A

IPEX = immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

ALPS = autoimmune lymphoproliferative syndrome

FHL = familial hemophagocytic lymphohistiocytosis

47
Q

What is IPEX?

A

A mutation in the Foxp3 gene that encodes a vital transcription factor for regulatory T cells.
This causes dysregulated immunity and self-reactive T cells are free to cause autoimmune Disease.

48
Q

What is ALPS?

A

A mutation in Fas or FasL that prevents the normal apoptosis in lymphocytes.
This causes uncontrolled lymphocyte proliferation, enlarged spleen and lymph nodes and autoimmunity or cancer.

49
Q

What is familial hemophagocytic lymphohistiocytosis?

A
  1. Mutation in one of several genes that causes defective release of lytic granules from CD8 and NK cells.
  2. Lymphocytes expand in response to infection but cannot mount a cytotoxic response. They still release IFNy.
  3. IFNy activates massive amounts of Macrophages.
  4. This causes phagocytosis of blood elements and tissue damage.
  5. It is often fatal
50
Q

What is a syndrome?

A

a group of symptoms consistently appearing together

51
Q

what is a immunodeficiency syndrome?

A

A heterogeneous group of disorders with both immune and extra immune manifestations.

52
Q

What is hereditary ataxia telangiectasia?

A
  1. Chromosomal breaks at TCR or IgH genes
  2. 70% of people have an IgA deficiency
53
Q

What is Wiskott-aldrich syndrome?

A
  1. WASp protein in the cytoskeleton
  2. Defective immune synapse formation
54
Q

What is hyper IgE syndrome?

A
  1. mutation in the STAT3 protein (which functions in response to IL-6 and IL-10)
  2. Th17 cells are impaired
55
Q

Phagocyte developmental defects: severe congenital neutropenia

A
  1. Caused by a variety of mutations
  2. severe lack of neutrophils in the blood.
  3. Overwhelming bacterial infection
56
Q

What are the phagocytes?

A
  1. Macrophages
  2. Monocytes
  3. Dendritic cells
  4. Granulocytes like neutrophils
57
Q

What are 2 examples of defects in phagocyte function?

A
  1. Chronic granulomatous disease
  2. Leukocyte adhesion deficiency
58
Q

What is chronic granulomatous disease?

A
  1. A deficiency in the NADPH oxidase enzyme.
  2. Without NADPH phagocytes cannot make superoxide anions or hydrogen peroxide in their phagosomes.
  3. This causes microbes to persist in the phagosome and granulomas to form.
59
Q

What are patients with chronic granulomatous disease susceptible to?

A
  1. Bacterial especially mycobacterial infections.
  2. fungal infections
60
Q

What is leukocyte adhesion deficiency?

A
  1. LAD1: mutations in the CD18 gene which is part of many phagocyte cell surface receptors.
  2. This causes defective complement receptor 3 and defective LFA-1
  3. Patients develop severe bacterial infections
61
Q

What does CR3 do?

A

binds to opsonised microbes to aid phagocytes

62
Q

What does LFA-1 do?

A

A cell adhesion molecule that allows phagocytes to migrate from blood vessels to sites of infection

63
Q

What is the most common cause of immunodeficiency globally?

A

Malnutrition

64
Q

What does malnutrition cause?

A

50% of childhood deaths

65
Q

How does malnutrition cause immunodeficiency?

A
  1. The immune response needs a lot of energy.
  2. The immune response is severely impaired of calories, macronutrients or vital micronutrients are limited.
66
Q

What is the cycle of malnutrition and infection?

A

Malnutrition = depletion of immunity = disease = decreased intake and absorption of nutrients = more malnutrition = more infection

67
Q

Immunodeficiency caused by drugs

A

Many drugs suppress the immune system either deliberately or as unwanted side effects.

68
Q

Why would we want to suppress the immune system?

A
  1. post organ transplant to suppress graft versus host disease.
  2. to prevent inflammatory, allergic or autoimmune reactions
69
Q

What are Glucocorticoids?

A
  1. They reduce the secretion of inflammatory cytokines like IL-1, IL-6, IL-8, TNF, and IL-12.
  2. prevent mast cell degranulation
  3. reduce dendritic cell activation and in turn T cell activation
    HOWEVER
  4. there are serious side effects with prolonged use
70
Q

What is the 2nd most common cause of immunodeficiency worldwide?

A

HIV causing AIDS

71
Q

What is HIV?

A
  1. A retrovirus that targets CD4 T cells, dendritic cells and macrophages.
  2. infected 30+ million people
  3. ~2 million death annually
  4. Without treatment the immune system is severely depleted and AIDS develops
72
Q

What are the first signs of AIDS?

A
  1. below 500 CD4+ T cells /µl of blood
  2. Susceptible to less severe conditions.
  3. Oral candidiasis, herpes virus outbreaks, pneumococcal infection
73
Q

What are the final stages of AIDS?

A
  1. Below 200 CD4+ T cells/µl of blood.
  2. Susceptible to life-threatening infections and malignancies.
74
Q

Common diseases with AIDS: Kaposi sarcoma

A

a malignant lesion that is a result of reduced immune surveillance

75
Q

Common diseases with AIDS: Pneumocystis jirovecii

A

A yeast infection that causes pneumonia

76
Q

Common diseases with AIDS: cryptosporida infection of the gut mucosa

A

from drinking infected water

77
Q

Common diseases with AIDS: Cerebral toxoplasmosis

A

Different neurological defects caused by out of control immunity

Cellular and Molecular pathology (25 decks)

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