Lecture 13 - Kung

Question 1

What are the two major types of immunodeficiencies?

Answer 1

Congenital and acquired.

Question 2

Immunodeficiencies usually target one of three things; what are they?

Answer 2

B cells, T cells, and the innate immune system.

Question 3

In B cell deficiencies, what would be the most likely histopathological and laboratory abnormalities? What about most common infectious consequences?

Answer 3

Absent or reduced follicles in germ centers in lymphoid organs. and reduced serum Ig levels.

Pyogenic bacterial infections

Question 4

In T cell deficiencies, what would be the most likely histopathological and laboratory abnormalities? What about most common infectious consequences?

Answer 4

Reduced T cell zones in lymphoid organs. Reduced delayed type hypersensitivity reactions to common antigens. Defective T cell proliferative responses to mitogens in vitro.

Viral and other intracellular microbial infections and other virus associated malignancies like EBV.

Question 5

In innate immune deficiencies, what would be the most likely histopathological and laboratory abnormalities? What about most common infectious consequences?

Answer 5

Abnormalities would be variable depending on which component was defective.

Likely to be pyogenic bacterial infections.

Question 6

What are the four types of congenital immunodeficiencies?

Answer 6

Defects in lymphocyte maturation
Defects in lymphocyte activation/function
Defects in innate immunity
Lymphocyte abnormalities associated with other diseases

Question 7

Congenital immunodeficiencies are AKA _________ immunodeficiencies.

Answer 7

Primary

Question 8

What are the four main defects in lymphocyte maturation?

Answer 8

X-linked SCID
Autosomal SCID
X-linked agammaglobulinemia
DiGeorge syndrome

Question 9

What does SCID stand for?

Answer 9

Severe combined immune deficiency

Question 10

What is X-linked SCID?

What causes it?

Answer 10

It is a set of disorders manifesting as defects in both the B cell and T cell arms of the adaptive immune system based on being linked to the X chromosome.
It is caused by mutations in a signaling subunit of a receptor for cytokines - the common gamma chain (gamma c)

Question 11

What kind of changes are present in someone with X-linked SCID?

Answer 11

Profound decrease in numbers of mature T and NK cells. Defect in B cell responses.

Question 12

What is gamma c?

Answer 12

it is a component of the receptors for numerous cytokines including ILs 2, 4, 7, 9, and 15.

Question 13

What is the result of defective…
responses to IL-7?
responses to IL-15?
proper T cell help?

Answer 13

Reduces survival and maturation of lymphocyte precursors.
Blocking NK development.
Defective B cell responses.

Question 14

What are the two more common autosomal SCIDs?

Answer 14

ADA and RAG 1/2 deficiency

Question 15

What does ADA deficiency stand for and what is it?

Answer 15

It stands for adenosine deaminase deficiency and it is an autosomal SCID caused by mutations in an enzyme called ADA which is involved in the breakdown of purines.

Question 16

What are the consequences of ADA deficiency?

What kind of cells are susceptible to this?

Answer 16

Leads to the accumulation of toxic purine metabolites in cells that are actively synthesizing DNA.
Proliferaing lymphocytes are susceptible therefore a block in T cell maturation. Somehow, B cell maturation is less affected.

Question 17

What is a RAG-1/2 deficiency?

What are the consequences of this?

Answer 17

An autosomal SCID caused by mutations in RAG1 or RAG2 gene which encodes for VDJ recomninase required for Ig and TcR gene recombination and maturation.
B and T cell development is blocked but NK cells are normal.

Question 18

DiGeorge syndrome is AKA ________ deletion.

Answer 18

22q11.2

Question 19

What is DiGeorge syndrome?

Answer 19

The most frequent, selective defects in T cell maturation. It results from incomplete development of the thymus and a failure of T cells to mature.

Question 20

Patients with DiGeorge syndrome tend to improve with age, why is this?

Answer 20

Probably because the small amount of thymic tissue that does develop is able to support some T cell maturation.

Question 21

What is X-linked agammaglobulinemia?

Answer 21

The most common clinical syndrome caused by a block in B cell maturation. B cells in the bone marrow fail to mature beyond the pre-B cell stage.

Question 22

What is the genetic cause of X-linked agammaglobulinemia?

Answer 22

Mutations in the gene encoding a kinase called the B cell tyrosine kinase or Btk. This results in defective production or function of the enzyme, the gene for which is located on the X chromosome.

Question 23

What are the treatments for defects in lymphocyte maturation?

Answer 23

The treatments available for each disease varies by disease and severity.

Question 24

What are the treatments for X-SCID?

Answer 24

X-SCID is fatal early in life unless the patient’s immune system is reconstituted. The most widely used treatment is bone marrow transplantation.

Question 25

How can we treat for B cell defects? | Which lymphocyte maturation disease can be helped by this?

Answer 25

Patients may be given pooled Ig from healthy donors for passive immunity. X-linked agammaglobulinemia is aided by this.

Question 26

What is the most ideal treatment for congenital immunodeficiencies?

Answer 26

Replacement gene therapy

Question 27

What what stage to defects in lymphocyte activation and function come about?

Answer 27

They affect mature B and T cells post positive/negative selection.

Question 28

What are the diseases considered to be under the umbrella of defects in lymphocyte activation and function?

Answer 28

X-linked hyper-IgM syndrome Common variable immunodeficiency The bare lymphocyte syndrome

Question 29

Describe X-linked hyper-IgM syndrome. What does it cause? What is it caused by?

Answer 29

Defective B cell heavy chain isotype switching occur so that IgM is the major serum antibody. This causes severe deficiency of cell mediated immunity against intracellular microbes. It is caused by mutations in the CD40L on the T cells that lead to defective T cell dependent B cell responses (isotype switching in humoral immunity) and defective T cell-dependent macrophage activation in cell mediated immunity.

Question 30

Describe common variable immunodeficiency. By what are they caused? What are their consequences?

Answer 30

It is a heterogeneous group of disorders that represent a common form of primary immunodeficiency - lots of things under one umbrella. Patients suffer from recurrent infections, autoimmune disease, and lymphomas. The cause of these are poorly understood but include defects in B cell maturation and activation. Disorders characterized by poor Ab responses to infections and reduced IgG, IgA, and IgM.

Question 31

Briefly describe bare lymphocyte syndrome. | By what are they caused?

Answer 31

``` The disease manifests by presenting a profound decrease in CD4+ T cells because their maturation is defective. Caused by a failure to express class II MHC molecules as a result of mutations in transcription factors that normally induce expression. ```

Question 32

What molecules, cytokines, or receptors might be involved in selective T cell deficiency of Th1 cells?

Answer 32

IL-12 and IFN gamma

Question 33

What molecules, cytokines, or receptors might be involved in selective T cell deficiency of Th17 cells?

Answer 33

IL-17 and IL-17 R

Question 34

Name the diseases under the umbrella of defects in the innate immunity.

Answer 34

Chronic granulomatous disease Deficiencies of complement protein Chédiak-Higashi syndrome Defects in TLR signaling

Question 35

Describe chronic granulomatous disease. What causes it? What are the consequences of this disease.

Answer 35

It is a disease regarding defects in the the innate immunity. It is caused by mutations in the enzyme phagocyte oxidase which catalyzes the production of microbicidal reactive oxygen species in lysosomes. Neutrophils and macrophages that phagocytose microbes are unable to kill the microbes and the immune system tries to compensate for this by calling in more macrophages and activating T cells which stimulates recruitment of even more phagocytes overloading the area.

Question 36

Describe deficiencies in complement protein. By what are they caused? What do they cause?

Answer 36

They are a disease characterized by defects in the innate immunity which affect C2, C3, and C4 and often caused by frameshift mutations. Deficiencies can result in severe infections and be fatal.

Question 37

Deficiencies in other components regulating complement activation are also very serious. What can they cause and how?

Answer 37

They can result in immune complex-mediated diseases like type III hypersensitivities which resemble lupus due to excessive complement activation.

Question 38

Describe Chédiak-Higashi syndrome and its cause and effects.

Answer 38

It is an immunodeficiency disease which lacks lysosomal granule function in leukocytes. Caused by mutation in LYST gene (lysosomal trafficking regulator). Defects in phagocytes and NK cells manifests by increased susceptibility to bacterial infections.

Question 39

Describe Wiskott-Aldrich syndrome.

Answer 39

An X-linked disease which causes immunodeficiency due to a mutation is the WAS protein gene (WASP gene) that encodes proteins that bind to various adapter molecules and cytoskeletal components in hematopoietic cells. It is characterized by eczema, reduced blood platelets, and immunodeficiency. Platelets and leukocytes are small and do not develop normally and fail to migrate normally.

Question 40

Describe Ataxia-telangiectasia.

Answer 40

Characterized by gait abnormalities (ataxia), vascular malformation (talangiectasia), and immunodeficiency. Disease caused by mutations in ATM gene whose product is involved in DNA repair.

Question 41

What do defects in the ATM gene do?

Answer 41

Defects in the gene are involved in DNA repair which would cause abnormal repair and result in defective lymphocyte maturation.

Question 42

What are the two main acquired immunodeficiencies?

Answer 42

Cancers involving the bone marrow and therapies for same | HIV infection

Question 43

How does cancer of the bone marrow allow someone to acquire an immune deficiency?

Answer 43

Chemo drugs and irradiation may damage proliferating cells including lymphocyte precursors and mature lymphocytes = immune deficiency.

Question 44

What kinds of therapies are able to give someone an acquired immune deficiency?

Answer 44

Treatments to prevent graft rejection often involve immune suppression and can be complicated by an increased immune suppression and acquired immunodeficiency.

Question 45

What is a common cause of acquired immunodeficiency in developing countries?

Answer 45

Protein-calorie malnutrition.

Question 46

How does protein-calorie malnutrition result in acquired immunodeficiencies?

Answer 46

It causes deficiencies of virtually all components of the immune system as it has no fuel to run. Metabolic derangements inhibit lymphocyte maturation and function.

Question 47

How can the removal of the spleen cause acquired immunodeficiency?

Answer 47

Decreased phagocytosis of microbes.

Question 48

Briefly describe the life cycle of HIV.

Answer 48

``` Infection of cells Production of viral DNA Integration into host genome Expression of viral genes Production of viral particles ```

Question 49

How would you describe the type of infection HIV creates in terms of intensity over time?

Answer 49

HIV is a latent infection starting out small and gradually growing over time as viral load increases.

Question 50

What is the clinical and pathological manifestation of AIDS?

Answer 50

Pronounces loss of immune system function and many opportunistic infections as a result of susceptibility and cancers from immune deficiency.

Question 51

What is the depletion of CD4+ T cells due to in HIV infection?

Answer 51

Loss of cells occurs due to cytopathic production of viral particles as well as death of uninfected cells.

Question 52

Does HIV affect cells other than T cells?

Answer 52

Yes! HIV can infect DCs and macrophages as they have been shown to express CD4 as well. They can die resulting int he destruction of the architecture of lymphoid organs.

Question 53

What is the clinical latency of HIV?

Answer 53

Once the virus infects the host it makes great attempts to stay hidden to avoid immune response and slowly increases viral load without triggering the immune system. While the host is infected but unknowing and unsymptomatic, this is clinical latency.

Question 54

What is the current treatment for AIDS?

Answer 54

HAART or cART

Question 55

What do HAART and cART stand for?

Answer 55

Highly active antiretroviral therapy | combination antiretroviral therapy

Question 56

What are some of the main challenges is developing an HIV vaccine?

Answer 56

The immune response to HIV is ineffective in controlling the spread of the virus and effects so vaccines would do little. Andibodies against GP120 may be ineffective due to massive mutation rate. CTLs are often ineffective because virus inhibits expression of MHC I. Immune responses may promote instead of inhibit HIV as it infects lymphocytes and increased lymphocytes may increase spread.