| What are the types of congenital defects in the innate immune system? | Defects in phagocytosis
• Defects in the complementsystem
• Defects in NK cells and other leukocytes
• Defects in leukocyte adhesion
5. Severe combined immunodeficiencies |
| What are some of the proteins affected by mutations that may block the maturation of T and B lymphocytes in human immunodeficiency diseases? | Janus kinase 3 (JAK3) is a kinase involved in signaling by many cytokine receptors; ARTEMIS is a protein involved in antigen receptor gene recombination; Bruton tyrosine kinase (BTK) is a kinase that delivers signals from the pre–B cell receptor and BCR; ZAP70 is a kinase involved in TCR signaling; and TAP proteins transport peptides for presentation by class I MHC molecules.
ADA, Adenosine deaminase; CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; PNP, purine nucleoside phosphorylase; RAG, recombination-activating gene; TCR, T cell receptor. |
| Examples of mutations that lead to hyper IgM syndrome | Caused by mutations in the X chromosome gene encoding CD40 ligand (CD40L) expressed in T cells
mutations affecting the enzyme activation-induced deaminase (AID), which is involved in B cell isotype switching and affinity maturation |
| What are some of the mutations that may block activation or effector functions of both mature CD4+ T cells and B cells, and what are the clinicopathologic consequences of these mutations? | -defects in various genes involved in B cell maturation and activation or in T-B cell collaboration. mutations in genes encoding receptors for B cell growth factors or costimulators that play a role in T cell–B cell interactions. Causes Common variable immunodeficiency (CVID) is a heterogeneous group of disorders that are characterized by poor antibody responses to infections and reduced serum levels of IgG, IgA, and sometimes IgM.
-mutations in the transcription factors that normally induce class II MHC expression. Causes bare lymphocyte syndrome a disease caused by a failure to express class II major histocompatibility complex (MHC) molecules. The disease is manifested by a profound decrease in CD4+ T cells because of defective maturation of these cells in the thymus and poor activation of the cells in peripheral lymphoid organs.
-mutations affecting various signaling pathways or cytokines and receptors involved in differentiation of naive T cells into effector cells. affected patients show severe T cell deficiency or deficiency in particular arms of T cell–mediated immunity, such as in Th1.
-genetic disorders in which cytotoxic CD8+ T cells and NK cells are unable to kill virus-infected target cells. causes Hemophagocytic lymphohistiocytosis (HLH) syndromes characterized by systemic, sometimes life-threatening, activation of immune cells including macrophages, usually in response to infections.
-mutations in the gene encoding perforin as well as mutations in genes that encode proteins involved in granule exocytosis. These mutations result in persistent infections, usually viral, and excessive production of IFNγ by T cells and NK cells, which in turn causes excessive macrophage activation |
| How does HIV infect cells and replicate inside infected cells? | • Virus bind to CD4 T cells via viral coat proteins (gp120 and gp41)
• Viral receptor on T cells includes CD4 receptor and chemokine receptors
• Once inside cell, viral enzymes activate and begin the viral reproductive cycle
• Viral RNA is reverse-transcribed into DNA by reverse transcriptase
• Viral DNA integrates into host DNA by enzyme integrase
• Integrated viral DNA can remain latent for years
• Viral LTRs and host cytokines trigger viral replication
• viral particles are assembled following full-length viral RNA and proteins are made
• Viral particles are released following destruction of host CD4 T cells |
| What are the principal clinical manifestations of advanced HIV infection, and what is the pathogenesis of these manifestations? | The clinical course of HIV infection typically consists of acute viremia, clinical latency with progressive destruction of CD4+ T cells and dissolution of lymphoid tissues, and ultimately AIDS, with severe immunodeficiency resulting in opportunistic infections, some cancers, weight loss, and occasionally dementia. Treatment of HIV infection is designed to interfere with the life cycle of the virus. Vaccine development is ongoing. |
| What does defects in phagocytes cause? | can lead to infections of skin, respiratory tract infection with bacteria (Staphylococcus aureus) or fungi (Aspergilus fumigatus, Candida albicans), oral stomatitis, etc. |
| What does Defects in the complement system cause? | defective C2 and C4 molecules (involved in classical pathway of complement activation) develop systemic lupus erythematosus
Deficiencies in the alternative complement pathway (i.e. Properdin) results in increased susceptibility to infection with piogenic bacteria* (possible cause, inability to form C3b which is required to opsonise bacteria)
deficiencies in the complement components C5 to C9 suffer diseminated infections with Neisseria meningitidis and N. Gonorrhoeae. |
| What does Defects in NK cells and other leukocytes cause? | Autosomal recessive disorder cause by a mutation of a gene (called LYST) involved in lysosomal trafficking
affects NK cells function due to abnormalities in the formation of cytoplasmic granules that mediate cytotoxicity by NK cells |
| What does Defects in leukocyte adhesion cause? | Leukocyte ahesion deficiencies (LADs) 1, 2 and 3.
fail to migrate to the infection sites due to defects in adhesion
LDA-1. It is caused by mutations in CD18 gene of β-2 integrins
LDA-2. A mutation in the fucose transporter to the Golgi apparatus.
LDA-3. A defect that inhibits signal transduction in integrins. Lack of integrin activation results in reduced ability of leukocytes to bind endothelial cells to extravasate |
