Week 2: Lec 5

Question 1

Primary Immunodeficiency (PID)

• What is it?
• It is also known as?

Answer 1

-What is it?
inherited immune disorders resulting from genetic mutations, usually present at birth and diagnosed in childhood.

• It is also known as: Inborn errors of immunity

Question 2

Primary Immunodeficiency (PID)

• Immune Defects

Answer 2

-Immune defects:

• Genetic Defects in Innate Immunity: involves abnormalities in phagocytes and complement

A) Chronic Granulomatous Disease (CGD): malfunctioning macrophages and neutrophils are unable to kill certain microorganisms

B) Leukocyte Adhesion Deficiency: complement deficiencies and malfunction of integrins and selectins which prevent leukocytes from vascular adherence to move to AG invasion site.

C) Chediak-Higashi Syndrome: lysosomal
granules of leukocytes function abnormally.

• Genetic Defects in Lymphocyte maturation:
A) Severe combined immunodeficiency (SCID):
Both B & T cell defects of adaptive immunity
-X linked SCID: affects male children; results in defective cell mediated and humoral immunity
-DiGeorge Syndrome: deletion of Chromosome 22 and interferes with development of Thymus and Parathyroid gland

B) Selective B cell deficiency:
- X linked agammaglobulinemia: Marked decrease in mature B cells and immunoglobulins due to failure to mature in bone marrow.

• Defects in Lymphocyte Activation and Function:

A) Defects in B lymphocyte response:
- X-linked hyper - IgM syndrome: defective B cell heavy chain isotype switching that results to IgM as major immunoglobulin and defective cell mediated immunity(CMI) against intracellular microbes.

B) Defects in activation of T lymphocytes:
- Bare Lymphocyte Syndrome: Mutation that fails to express Class II Major Histocompatibility Complex (MHC) & prevents AG recognition by CD4+ T cells; results in reduced CD4+T cells & their maturation; reduced CMI

Question 3

Secondary (Acquired) Immunodeficiencies [SAID]:

• What is it?
• Causes & mechanism

Answer 3

Immune system deficiencies acquired through life that are not due to genetic immune disorders.

Causes:

(a) Infectious diseases:
- HIV: Depletion of CD4+ helper T cells
(b) Malnutrition: Inhibit lymphocyte maturation and function
(c) Genetic and metabolic diseases:
- Involvement of bone marrow by cancers: Reduced site of leukocyte development
(d) Immunosuppressive drugs: Depletion or functional impairment of lymphocytes
(e) Surgery and Trauma splenectomy:
- Removal of spleen: decreased phagocytosis
- Irradiation and chemotherapy treatments for cancer: decreased bone marrow precursors for all leukocytes
(f) Age extremes (Prematurity and old age)
(g) Environmental stress

Question 4

Transplant Immunology

-What is allotransplantation?

Answer 4

Allotransplantation:
Transplantation of cells, tissues or organs from a donor that is not genetically identical to the recipient (host) but of the same species.

Question 5

Response to allograft:

Allorecognition of T cells

Answer 5

• Self antigens (histocompatibility AG on human leukocytes & tissues): allow host’s immune system to detect difference between self from foreign cells
• Allorecognition of T cells:
  (a) Direct Recognition of Alloantigens: occurs when the T cell binds directly to intact allogenic major histocompatibility complex (MHC) molecules found on antigen presenting cells in the allograft

2 )Indirect alloantigen recognition occurs when allogenic MHC molecules from the graft are acknowledged and processed by the recipients APC and peptide fragments are presented by recipient(self) MHC molecule to T cell. allogenic MHC molecules.

-Indirect allorecognition predominates late phase, post transplantation immune response

Question 6

Immune response against transplants: No immunosuppressant medications

Answer 6

1. After transplant, the allograft antigens that are expressed on donors dendritic cells(DC) or captured by recipient’s DC are transported to peripheral lymphoid organs by afferent lymph vessel.
2. Sensitization: In the recipient’s lymph node, alloantigen-specific T cells are activated by Sensitization. Cytokines are released.
3. Rejection: The sensitized T cells migrate back to the allograft and destroy the graft cells resulting in a Rejection of the allograft.
   a) This rejection occurs due to the development of cell-mediated immune response (mediated by TH) against Class II HLA on graft.
   b) Either acute or chronic rejection may occur.

4.Antibodies through humoral immunity are also produced against graft antigens and then contribute to a humoral rejection

Question 7

Rejection Immunology:

Types & description

Answer 7

A) Hyperacute Rejection: Preformed antibodies react
with alloantigens on vascular endothelium of graft, activate complement and trigger immediate intravascular thrombosis and necrosis of the vessel wall and allograft dysfunction.

(B) Acute Rejection:

• can occur days to years after transplant
• occurs due to development of cell-mediated immune response against class II HLA on graft
• CD8+ lymphocytes react with alloantigens on graft endothelial cells and parenchymal cells or antibodies react with endothelial cells (humoral) and result in damage to these cells and the allograft.
• –MOST COMMON FORM OF REJECTION

C) Chronic Rejection: with allograft arteriosclerosis, T cells react with graft alloantigens and may produce cytokines that induce inflammation and proliferate intimal smooth muscle cells resulting in luminal occlusion and gradual allograft dysfunction.