Immunodeficiency Flashcards
Bruton agammaglobulinemia was the first
primary immunodeficiency disease to be described.
In 1952, Colonel Ogden Bruton noted the absence of
immunoglobulins in a boy with a history of pneumonias and other bacterial infections.
Dr Bruton was also the first physician to provide specific immunotherapy for this X-linked disorder by administering intramuscular injections of immunoglobulin G (IgG).
Primary or congenital immunodeficiencies: are
genetic defects that result in an increased susceptibility to infection
Primary or congenital immunodeficiencies: is frequently manifested in
infancy and childhood.
Primary or congenital immunodeficiencies: such diseases affect about
1 in 500 people in the United States
Secondary or acquired immunodeficiencies
develop as a consequence of
malnutrition,
disseminated cancer,
treatment with immunosuppressive drugs, or
infection of cells of the immune system.
Integrity of the immune system is essential for defense against
nfectious organisms and their toxic products. Thus, the immune system is important for our survival!!!
Toll-Like Receptors are conserved across
widely diverse species!!!
Any loss-of-function mutation affecting a TLR has negative consequences for survival
Primary (or genetically determined) immunodeficiency disorders may
affect one or more components of the immune system, including T-, B-lymphocytes, and Natural Killer cells, as well as phagocytic cells and complement proteins.
Immunodeficiencies may result from
defects in leukocyte maturation or activation or from defects in effector mechanisms of innate and adaptive immunity.
The principal consequence of an immuno-deficiency is an increased susceptibility to
infection:
The nature of the infection in a particular patient depends largely on
the component of the immune system that is defective.
In other words, the types of recurring infections can predict the
type of immunodeficiency.
Deficient humoral immunity usually results in
increased susceptibility to infection by pyogenic bacteria.
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia)
All Antibody Isotypes are
very low – not even IgM or IgD
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia):
Circulating B cells are usually
absent.
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia):
Pre-B cells are present in
reduced numbers in the bone marrow.
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia):
Tonsils are usually very
small and lymph nodes are rarely palpable due to absence of germinal centers.
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia):
Thymus architecture is
normal, as are the T cell-dependent areas of spleen and lymph nodes.
X-linked Agammaglobulinemia - XLA(also known as Bruton’s Agammaglobulinemia): Most boys afflicted with X-linked agammaglobulinemia (XLA) remain
well during the first 6 to 9 months of life by virtue of maternally transmitted IgG antibodies. Thereafter, they repeatedly acquire infections with extracellular pyogenic organisms such as pneumococci, streptococci, and haemophilus
X-linked Agammaglobulinemia
1) Circulating B cells are usually absent. 2) Pre-B cells are present in reduced numbers in the bone marrow
The defect in this disease is associated with a loss of function of
Bruton Tyrosine Kinase that is important for pre-B cell expansion and maturation into Ig-expressing B cells
X-linked immunodeficiency with hyper-IgM is characterized by
very low serum IgG, IgA, and IgE
a markedly elevated concentration of polyclonal IgM
Like boys with XLA, patients with hyper-IgM may become
symptomatic during the first or second year of life with recurrent pyogenic infections
These include otitis media, sinusitis, pneumonia, and tonsillitis.
In contrast to patients with XLA, however, hyper-IgM patients have
lymphoid hyperplasia.
X-linked immunodeficiency with hyper-IgM:
The defect in this disease is associated with a loss of function of
CD40 ligand (aka CD154) that is expressed on helper T cells.
The loss of this molecule prevents the T cell from co-stimulating antigen-specific B cells (through CD40).
Thus, B cells are not signaled by the T cell to go through isotype switching and only produce IgM.
Immunodeficiency Treatment is routine –
prophylactic antibiotics and/or gamma-globulin therapy.
Dr. Ogden Bruton pioneered this therapy.
Deficient cell-mediated immunity usually results in
increased susceptibility to viruses and other intracellular pathogens.
Whereas treatment of deficiencies of the humoral immune response may be routine, there are few if any treatments for
defects associated with deficient T cell responses.
In fact, it is rare that patients with absolute defects in
T-cell function survive beyond infancy or childhood.
DiGeorge’s syndrome : This is a developmentally-related disease associated with
tissue morphogenesis – the thymus does not develop.
DiGeorge’s syndrome: Thymic hypoplasia results from defects in
morphogenesis of the third and fourth pharyngeal pouches during early embryogenesis,
Other structures forming at the same age are also frequently affected, resulting in anomalies of the great vessels (right-sided aortic arch), esophageal atresia, bifid uvula, upper limb malformations, congenital heart disease (atrial and ventricular septal defects), a short philtrum of the upper lip, hypertelorism, an antimongoloid slant to the eyes, mandibular hypoplasia, and low-set, often notched ears.
DiGeorge’s syndrome: Immunologically speaking, the percentage of T cells is variably
decreased; as a result, there is a relative increase in the percentage of B cells.
B-cell function is impaired only to the extent of needing helper T cells.
DiGeorge’s syndrome: Most infants die from
infections, cardiovascular defects or seizures within the first few months or second year of life. Patients who survive infancy are usually mentally retarded.
There are clinical similarities between DiGeorge’s syndrome and fetal alcohol syndrome.
X-linked Recessive Severe Combined Immunodeficiency Disease:
Severe combined immunodeficiency is a
rare, fatal syndrome characterized by profound deficiencies of T- and B-cell function.
X-linked Recessive Severe Combined Immunodeficiency Disease: X-linked SCID (XSCID) is the most
common form, accounting for approximately 42% of cases.
X-linked Recessive Severe Combined Immunodeficiency Disease:
Affected infants present within the first few months of life with frequent episodes of
diarrhea, pneumonia, otitis, sepsis, and cutaneous infections.
X-linked Recessive Severe Combined Immunodeficiency Disease:
Growth may appear normal initially, but extreme wasting usually develops after
infections and diarrhea begin.
X-linked Recessive Severe Combined Immunodeficiency Disease :
Persistent infections with
opportunistic organisms
Candida albicans, Pneumocystis carinii, varicella, measles, parainfluenzae, cytomegalovirus, and EBV.
X-linked Recessive Severe Combined Immunodeficiency Disease :
These infants also lack the ability to reject
foreign tissue and are therefore at risk for GVHD.
GVHD can result from maternal T cells that cross into the fetal circulation while the SCID infant is in utero.
X-linked Recessive Severe Combined Immunodeficiency Disease: XSCID patients have few or no
T cells, and NK cells
X-linked Recessive Severe Combined Immunodeficiency Disease:
Patients with XSCID usually have
elevated percentages of B cells.
However, these B cells do not produce immunoglobulin normally, even after T-cell reconstitution by bone marrow transplantation.
Secondary or acquired immunodeficiencies
develop as a consequence of
malnutrition,
disseminated cancer,
treatment with immunosuppressive drugs, or
infection of cells of the immune system.
Treatment of Immunodeficiencies
Current treatments of immunodeficiences have two aims – 1. to minimize and control infections and 2. to replace the defective or absent components of the immune system by adoptive transfer and/or transplantation.
Passive immunization with pooled gamma globulin is enormously valuable for agammaglobulinemic parients and has been life saving for many with this disease.
Bone marrow transplantation is currently the treatment of choice for various immunodeficiency diseases and has been successful in the treatment of SCID and other similar diseases.
