Deficiencies of adaptive immunity Flashcards
What is a primary immunodeficiency?
In primary immunodeficiencies, are germline mutations show an immediate clinical phenotype?
In primary immunodeficiency:
There are intrinsic defects in the development and/or function of parts of the immune system. In many cases, primary immunodeficiency results from pathogenic genetic variants (or mutations) in immunologically important genes.
Typically, such variants are germline mutations, meaning they affect germline cells (or sex cells). As germline cells are affected, deleterious germline mutations result in a congenital disease.
However, it is important to note that germline mutations do not always result in an immediate clinical phenotype. Depending on the nature of the mutation, and what gene is affected, clinical manifestations of a congenital disease may not surface for several years (if not decades).
Also, there can be variable penetrance—the degree to which a mutation is expressed phenotypically— of the mutation, meaning individuals with these mutations may have symptoms along a spectrum of severity.
As a simple example, if the t_hymus or bone marrow_ were congenitally dysfunctional (due to a germline mutation) that would result in primary immunodeficiency.
Depending on the degree of said dysfunction, one individual may present with signs and symptoms sooner than another individual.
What is a secondary immunodeficiency?
Results due to what?
In secondary (or acquired) immunodeficiency, immunodeficiency may result from infection (HIV/AIDS), immunosuppressive therapy, malnutrition, or chronic/severe illness (such as advanced cancer).
Acquired immunodeficiency is secondary to another condition.
Is immunodeficiency temporal?
What is an example?
Immunodeficiency can be temporary or self-limited, as in transient hypogammaglobulinemia of infancy or during treatment with cancer chemotherapy drugs.
Alternatively, immunodeficiency can be permanent.
Primary immunodeficiency affecting the adaptive immunity
Primary immunodeficiencies resulting from defects in adaptive immunity result from abnormal development and/or function of T cells and/or B cells. It is largely by studying the clinical syndromes associated with immunodeficiency diseases that we know what T and B cells are really important for in humans.
Severe Combined Immunodeficiency Diseases, or SCID
What is SCID?
Children with SCID survive how long if untreated?
What are some notable findings?
- If there are low numbers of T cells (and possibly B and NK cells), it is as if there is a block in the development of lymphoid stem cells (common lymphoid progenitors, CLP), or their maturation. These conditions are the most devastating of the immunodeficiency states and are, as a whole, referred to as Severe Combined Immunodeficiency Diseases, or SCID.
-In the general population, SCID occurs with an incidence of about 1 in 50,000 births.
-Children with SCID rarely survive untreated beyond a year of life (they are, to some extent, protected in the neonatal period by maternal IgG).
Notable findings include lymphopenia of T cells (with variably low B and NK cells, depending on the underlying defect), an absent thymic shadow on X-ray (due to low or absent T cells), and small-to-absent tonsils/lymph nodes (due to low or absent B cells).
-Mitogen responses and serum immunoglobulins are typically low.
What is the most common SCID?
What is its mode of inheritance?
The defect in in the _______ that forms part of the receptor for ________.
What is the phenotype?
Which cells are normal or high?
The most common form of SCID is X-linked (also known as X-linked SCID or SCID-X1).
In SCID-X1, the defect is in ►the gene for the common gamma chain that forms part of the receptor for interleukin-2 (IL-2) and other interleukins. These interleukin receptors are necessary for lymphocyte development and/or signaling.
SCID-X1 results in an immunologic phenotype of low T cells and NK cells but often normal (or high) numbers of B cells.
In addition to SCID-X1, there are several other genetic causes of SCID, all of which have an ____________ inheritance pattern. One autosomal recessive type of SCID is adenosine deaminase (ADA) deficiency. In ADA deficiency, patients lack the ADA enzyme, resulting in accumulation of toxic ________ metabolites in lymphocytes that in turn inhibit DNA synthesis (and thus proliferation/survival).
autosomal recessive
Adenosine
What is X-linked (Bruton’s) agammaglobulinemia (or XLA) ?
Patients usually have what in their bone marrow?
Except for _____, all the other immunoglobulins are virtually undetectable.
What is the defect?
What type of infections are common in these patients?
If there are normal T cells but low to absent B cells, it may be that there is a developmental block In B cell development.
XLA patients (boys) have pre-B cells in their bone marrow but are deficient in circulating B cells and antibody production (serum IgG less than 10% of normal; IgA, IgM, and IgE are virtually undetectable).
This disease results from a defect in a protein tyrosine kinase gene, called btk, which is imperative for B cell development beyond the pre-B cell stage.
XLA patients often suffer from recurrent sinopulmonary infections (such as sinusitis and pneumonia) as well as chronic infectious diarrhea. Enteroviruses, which gain entry through mucous membranes unprotected by the absence of secretory IgA, may also be a problem; among these is poliovirus.
XLA patients are one of the reasons we no longer use the oral polio vaccine in the US, as the oral polio vaccine (Sabin) contains a live-attenuated virus; US children now receive an inactivated (killed) polio vaccine (Salk) via intramuscular injection.
In addition to XLA, there are several other genetic causes of arrested B cell development. However, XLA is the most common monogenic (one gene affected) cause of agammaglobulinemia and absence of circulating B cells, with an incidence of 1 in 200,000 births.
Some patients have high IgM with low IgG, IgA, and IgE; in such patients, there is a defect in the IgM-to-IgG/A/E switch mechanism (also known as class switching).
What is th accesory molecule that Tfh have? Interacts with what of B cells?
What is hyper IgM syndrome?
CD40L deficiency is what type of inheritance?
CD40 is what type of inheritance?
The T follicular helper (Tfh) cell has an accessory molecule (CD40-ligand or CD40L) that interacts with CD40 on B cells, signaling the B cells to class switch (see diagram in T cell unit).
For example, if either CD40 or CD40L is defective, the B cell is unable to switch past making IgM.
This results in a hyper IgM syndrome.
Among the causes of hyper IgM syndrome are CD40L deficiency (X-linked) and CD40 deficiency (autosomal recessive).
CD40L deficiency (or X- linked hyper IgM syndrome) has an incidence of about 1 in every 1,000,000 births.
It can happen that there are normal numbers of pre-B cells and B cells, but the B cells are ineffective at making specific antibodies or making immunoglobulin at all. The most common of these conditions is called________________.
When is it commonly diagnosed?
What is the main clinical phenotype?
Common Variable Immunodeficiency (CVID)
CVID is a serious condition but is milder in severity than SCID and some of the other primary immunodeficiency diseases.
Though CVID is seen in children, many CVID patients are diagnosed in or after their second decade of life.
Similar to XLA patients, the main clinical phenotype is recurrent bacterial infections (often sinopulmonary).
CVID patients are at increased risk for malignancy, enteropathy, granulomatous liver/lung disease, and autoimmunity. Over the past few decades, there have been causative genetic mutations found in a small subset of these patients; however, the cause of CVID for many patients remains unknown.
Di George’s Syndrome
It is the result of a large deletion on chromosome_______.
What organ does not develop appropiately?
How does the parathyroid plays a role in detecting Digeorge’s syndrome?
What other parts of the heart develop abnormally as well?
DiGeorge Syndrome, which is typically the result of a large (45 gene) deletion on chromosome 22.
In this disorder, the thymus does not develop appropriately, resulting in a T cell immunodeficiency state.
For a small number of children with DiGeorge syndrome, the effect is profound (resulting in complete or near-complete absence of circulating T cells).
The parathyroids also derive from the pharyngeal pouches, so this diagnosis is sometimes made in infancy when there are unexplained convulsions that are controllable by calcium.
- The great vessels of the heart develop abnormally, too.
- Cell-mediated immunity is depressed; viral and fungal infections are relatively common.
Incidence of about 1 in every 1,000 fetuses. Nude mice have quite a different mutation (in a gene called FOXN1), but also fail to make thymic stroma (and hair); therefore, they have no T cells and are immunologically similar to those DiGeorge syndrome children with complete absence of a thymus.
Infections
T cell deficiencies are associated with severe infections with_________.
What are some common examples of microorganism that characterize infection in T cell deficiencies?
T deficiencies are associated with severe infections with intracellular pathogens:
- Viruses
- certain bacteria
- yeasts and fungi, especially *Candida albicans and *Pneumocystis jirovecii.
B cell deficiency is characterized by infections with “high-grade” (extracellular, pyogenic = pus-producing) bacterial pathogens such as ____________, _____________ and Streptococcus pneumoniae.
Staphylococcus aureus
Haemophilus influenzae
Infections
Defective NK cells result in _____1_____.
Defect in complement results in___2_____.
1- Viruses, specially human herpes virus
2- Bacteria
TRANSIENT HYPOGAMMAGLOBULINEMIA OF INFANCY:
When is this condition noticed? How long can it last?
Children are slow in producing what Ig?
What kind of bacterial infection do they commonly present with?
This is a self-limiting condition, noticed about 6 months after birth and lasting up to 18 months (in a few cases, much longer).
These children are slow to get their production of IgG going.
They present mostly with recurrent and/or persistent Gram-positive bacterial infections, but may get just about anything.
►Perhaps 15% of all chronic diarrhea in infants is due to this condition.
Treatment of immunodeficiency
Different tests for immunodeficiencies
