failure of the host defense mechanism - Primary immunodeficiency

when do immunodeficiencies occur?

Immunodeficiencies occur when one or more components of the immune system are defective.

How are immunodeficiencies detected?

generally detected clinically by a history of recurrent infections, often by the same or similar pathogens.

what are the two different classifications of immunodeficiency?

1. Primary immunodeficiency

2. Secondary immunodeficiency

what causes primary immunodeficiencies?

cause by inherited genetic defects involving genes which play important roles in immune responses. These mutations affect the development of immune cells, their function, or both.

are the gene defects that cause primary immunodeficiency dominant or recessive?

Most of them are recessive and many are found on the X chromosome

what causes secondary immunodeficiencies?

they are acquired as a result of a disease, environmental factors, or an adverse consequence of a medical intervention.

what is Severe combined immunodeficiency (SCID)?

a family of disorders that affects either T cells or both T and B cells (sometimes NK cells). Defects in T cell development alone can result in SCID.

what do patients with SCID NOT exhibit?

they do not exhibit cell-mediated immune response due to lack of T cells
(sometimes NK cells)

they do not exhibit T cell-dependent antibody responses due to lack of T cell help.

the major characterizing symptom of SCID

SCID patients are susceptible to a broad range of infectious agents.

characterized by severe and recurrent infections (bacterial, viral, fungal) that usually lead to death early in life.

What is the only treatment available to SCID patients?

bone marrow transplant

what is adenosine deaminase (ADA) deficiency?

An autosomal recessive form of SCID caused by defects in the enzymes of the salvage pathway of purine synthesis.

what does ADA do?

catalyzes the conversion of adenosine and deoxyadenosine to inosine
and deoxyinosine, respectively.

ADA deficiency results in the accumulation of deoxyadenosine and its precursor, S-adenosylhomocysteine, which are toxic to developing T and B cells.

what is X-linked SCID (XSCID)?

The most common form of SCID.

caused by mutations in the gene for IL-2 receptor common gamma chain (γc). The γc-chain is required in all receptors of the IL-2 cytokine family (IL-2, IL-4, IL-7, IL-9 and IL-15).

what does XSCID do?

T cells and NK cells fail to develop.

Patients with XSCID have normal numbers of B cells but due to the absence of T cell help, their function is not normal. They lack both cell-mediated and
humoral immunity.

What is jaunus kinase 3 (JAK3)

JAK3 is a kinase associated with the γc-chain and transduces signaling through the γc-chain cytokine receptors. Inactivating, autosomal recessive mutation in JAK3 impairs the development of T cells and NK cells, but not B cells. Clinically and phenotypically, the disease is similar to XSCID

how can defects in receptor gene rearrangement cause SCID?

Mutations in either the RAG1 or RAG2 genes arrest lymphocyte development at the DN to DP thymocyte, and pro- to pre-B cell transition because of a failure of V(D)J
recombination. This results in a complete lack of both T cells and B cells in these patients. NK cell development is not affected.

what is Omenn syndrome?

Hypomorphic mutations in RAG1 or RAG2 genes result in reduced but not total absence of functional RAG1 or RAG2, allowing limited TCR gene recombination. These patients have a limited TCR repertoire but no B cell

what causes radiation-sensitive SCID (RS-SCID)?

Cause by defects in ubiquitous DNA repair proteins (Artemis, DNA-PKc, DNA ligase IV) involved in repairing DNA double strand breaks generated during receptor gene rearrangement. Double stranded DNA breaks are also cause by ionizing radiation, hence, RS-SCID patients show increased sensitivity to ionizing radiations.

what is a defective CD3 complex?

Mutations in the CD3γ, CD3ε, and CD3ζ chains of the CD3 complex result in
defective pre-TCR signaling and failure to progress to the DP stage of thymic development. These patients lack T cells but not NK cells and B cells.

What is Wiskott-Aldrich syndrome (WAS) caused by?

WAS is caused by a defect in the WAS gene on the X chromosome that encodes WAS protein (WASp). WASp is involved in the transduction of signals from lymphocyte receptors for the reorganization of cytoskeleton and formation of the immune synapse. WAS is characterized by reduced T cell numbers, defective NK cell cytotoxicity, and a failure of B cell responses.

what is DiGeorge syndrome?

Thymic epithelium fails to develop normally due to a deletion within a copy of chromosome 22. The relevant gene within the deleted region is TBX1, which encodes the transcription factor T-Box 1. DiGeorge syndrome is cause by deletion of a single copy of this gene. Patients are haploinsufficient for TBX1 gene.

what causes defects in thymus development (athymic)?

Caused by mutation in the gene FOXN1, which encodes a transcription factor selectively expressed in skin and thymus. FOXN1 is essential for formation of a functional thymus.

what does a lack of thymic function do?

prevents T cell development, and B cell responses are deficient because of the
lack of T cell help

In mice, lack of thymic development is associated with lack of body hair, as seen with hairless mice.

How can defects in MHC expression cause SCID?

Lack of MHC molecules result in severe immunodeficiency as a result of effects on the positive selection of T cells in the thymus. When TCR on developing thymocytes are not engaged by MHC molecules, thymocytes development is arrested.

What is Bare lymphocyte syndrome or MHC class II deficiency?

CD4 T cells are not positively selected and only very few develop. MHC class I expression is normal and CD8 T cells develop normally.

Antigen presenting cells in these patients do not express MHC class II and the few CD4 T cells that do develop cannot be activated by antigens. Antibody responses are defective due to lack of T cell help.

what causes an MHC class I deficiency?

This condition arise due to mutations in TAP1 or TAP2 genes, which encode TAP
proteins responsible for transport of processed antigens into the endoplasmic reticulum where they can be loaded on MCH class I molecules.

In the absence of peptide loading, MHC class I molecules do not make it to the cell surface. Reduced levels of MHC class I on thymic epithelial cells result in reduced number of CD8 T cells being produced in the thymus.

what do people with a complete lack of MHC class I experience?

they are affected by chronic respirator bacterial infections and skin ulceration with vasculitis

What are some causes of B cell deficiencies?

• ADA

• RS-SCID

• defects in components of pre-B cell receptor components (μH, λ5, Igα, Igβ)

• defects in receptor signalling due to deficiencies of B cell linker protein (BLNK)

• Bruton’s tyrosine kinase (BTX).

What causes X-linked agammaglobulinemia (XLA)?

a defective gene which encode a protein tyrosine kinase called BTK (Bruton’s tyrosine kinase). BTK is required for signal transduction from the pre-B cell receptor. B cell development is arrested at pre-B cell stage resulting in B cell deficiency and agammaglubulinemia (absence of immunoglobulins in the serum)

What do B cell deficiencies to do people? How do you treat it?

Patients with B cell deficiencies are unable to cope with extracellular bacteria and some viruses due to their inability to produce antibodies.

the condition can be treated with antibiotics and injections of purified pooled human IgG, although sinopulminary infections persist due to a continued lack of secretory IgA

what do pyogenic bacteria have?

they have a polysaccharide capsule that inhibit direct recognition and phagocytosis by macrophages and neutrophils. Opsonization by antibody and complement enables phagocytes to ingest and destroy the bacteria.

Abnormal antibody responses due to defective antibody class switch:

A common feature of patients with a defect in class switching is hyper-IgM syndrome. These patients have normal or high levels of serum IgM but make very little of other antibody classes

What causes Hyper-IgM syndrome?

lack of T cell help during B cell activation. This can be cause by mutations which affect expression of
CD40 on B cells (hyper-IgM syndrome), or CD40L on helper T cells (X-linked hyper-IgM syndrome)

X-linked hyper-IgM syndrome can also be caused by NEMO (NFκB essential modulator) deficiency.

What is NEMO? (NFκB essential modulator)

an essential component of the signaling pathway downstream of CD40 that leads to the activation of the transcription factor NFκB

whats the deal with lymphoid tissues in hyper-IgM syndrome patients?

they are do not have a germinal centre due to the lack of proper B cell activation by the helper T cells

what is B cell intrinsic hyper-IgM syndrome?

Defects in activation-induced cytidine deaminase (AID) function in B cells cause class switch defect. AID is required for both somatic hypermutation and class switching. Patients with defective AID function also have greatly reduced somatic hypermutation

what are common variable immunodeficiencies (CVID)?

relatively mild and are due to defects in immunoglobulin production that are limited to one or more isotypes.

what is an IgA deficiency?

an example of CVID and is the most common primary immunodeficiency. In most patients, the etiology of IgA deficiency is not known. IgA-deficient patients who develop recurrent infections generally also have an associated defect in the IgG subclasses

what is hyper-IgE syndrome (HIES) aka Job’s syndrome?

HIES patients have a very high serum concentration of IgE. The cause of elevated IgE is not understood.

transcription factor SAT3 function (HIES)

one of the genetic defects in HIES patients affects transcription factor STAT3 function. STAT3 is activated downstream of several cytokine receptors.

STAT3 is also essential for differentiation of TH17 cells. Neutrophil recruitment, orchestrated by TH17 cells and production of IL-22, which activates epithelial cell production of antimicrobial peptides, is defective in HIES patients

what are the symptoms of HIES?

recurrent skin and pulmonary infection by pyogenic bacteria, chronic mucocutaneous candidiasis, and skin rash

Defects in the cytolytic pathway of lymphocytes:

Inherited defects in the cytolytic pathway of lymphocytes can cause uncontrolled lymphoproliferation
and inflammatory responses to viral infections

what is hemophagocytic lymphohistiocytic (HLH) syndrome?

HLH is a severe and often fatal condition, which manifests as uncontrolled activation and expansion of CD8 T cells and macrophages that infiltrate multiple organs, causing tissue damage and organ failure

what causes hemophagocytic lymphohistiocytic (HLH) syndrome?

caused by the inability of cytotoxic T cells to destroy infected target cells following an initiating viral infection, providing a continuous stimulus for immune activation

can be caused by defects in the components of the cytolytic granules, including perforin deficiency, which is the main mechanism by which cytotoxic T cell can kill infected target cells

Defects in myeloid lineage cells permit widespread bacterial infections:

Phagocyte immunodeficiencies can be due to deficiency in phagocyte production, phagocyte adhesion, phagocyte activation, or phagocyte killing or microorganisms

what is severe congenital neutropenia (SCN) or cyclic neutropenia?

Inherited deficiencies in neutrophil production. Cyclic neutropenia is characterized by fluctuation in neutrophil numbers from near normal to very low with an approximate cycle time of 21 days, resulting in periodicity of infection risk.

what causes severe congenital neutropenia (SCN) (or cyclic neutropenia)

The most common causes of SCN are mutations of the gene that encodes neutrophil elastase, a component of the primary granules. Altered targeting of defective elastase to granules cause apoptosis of developing myelocytes

what are leukocyte adhesion deficiencies (LAD) caused by?

caused by a failure to express the ß subunit (CD18) of the adhesion molecules, such as LFA-1, MAC-1. These adhesion molecules, which are required for cellular interactions, are nearly absent from the cell membrane

what are the symptoms of leukocyte adhesion deficiencies (LAD)?

Individuals with this defect exhibit impaired extravasation of neutrophils, monocytes and lymphocytes; impaired ability of CTL and NK cells to adhere to target cells; and failure of T helper cells and B cells to form conjugates

Frequent bacterial or fungal infections, the absence of pus formation, and impaired wound healing lead to premature death

what causes chronic granulomatous disease (CGD)?

CGD is caused by a defect in the oxidative pathway that phagocytes use to generate reactive oxygen and nitrogen species. As a result, phagocytes are unable to kill many types of phagocytosed bacteria, leading to excessive inflammatory responses, susceptibility to bacterial and fungal infections, and formation of granulomas

a way of treating some immunodeficiencies (hint: with a specific type of cell)

Hematopoietic stem cell (HSC) transplantation.

The donor and the recipient must share some HLA allele. Both T cells and APCs will develop from the grafted donor HSC in the recipient host.

The shared HLA allows T cells derived from the donor HSC to develop in
the recipient’s thymus. Newly developed T cells are MHC^b-restricted and can be activated by APCs
presenting antigens on MHC^b, and provide immunity when they encounter infected host cells expressing MHCb

what is gene therapy?

a potential alternative to treat some forms of SCID (e.g., ADA deficiency) but is only now in the experimental stage and has caused some serious problems (most notably leukaemia) due to the use of retroviral vectors