·
C1 is composed of
C1q, C1r, and C1s. To be activated, two of the five arms of C1q must
interact with binding sites located near the hinge region of IgG and IgM
molecules. Therefore, C1q activation requires two
adjacent IgG molecules or a single IgM molecule.
·
Hereditary
angioedema is an autosomal dominant disease due to a deficiency of
C1 inhibitor (C1INH). The family history and the lack of urticaria suggest the
diagnosis. Acquired C1 inhibitor deficiency
has the same clinical manifestations as the inherited form but is associated
with lymphoproliferative disorders and lacks the family history.
·
Activation of the alternative
pathway is initiated by binding of C3b
to the surface of antigens, particularly microbial membranes. The alternative
pathway bypasses C1, C2, and C4. Therefore,
measurement of C3 and C4 can give some indication as to whether the activation
has been via the classical (immune complex) or alternative (pathogen) pathways.
·
A third mechanism for activation of the
complement cascade is mediated by a protein that is structurally similar to C1q of the classical pathway. This protein, called
the mannose-binding lectin, reacts
with repeating carbohydrate residues on bacterial surfaces that are commonly
displayed by a wide array of microbes. Mannose-binding lectin employs C4 and C2 in an activation pathway that is
closely homologous to that utilized by the classical complement activation
pathway.
·
Activation of the complement cascade does not
proceed in fluids like blood plasma beyond C3 because enzymes in the blood
promptly degrade activated C3 that is not covalently attached to a membrane
structure or an antigen-antibody complex. In addition, mammalian
somatic cells, but not red cells, are protected against injury by activated
complement by three proteins, decay-accelerating factor, membrane
cofactor protein, and CD59, also called protectin. These
proteins interfere with the assembly of the enzymes that could otherwise
complete the complement cascade and lyse the cell.
·
IFN-alpha
is produced by leukocytes, fibroblasts.IFN-beta1,2
is produced by fibroblasts, leukocytes. IFN-gamma
is produced by activated T lymphocytes, natural killer (NK) cells, and
lymphokine-activated killer (LAK) cells.
Both IFN-alpha and IFN-beta1 (IL 6)
modulate antibody production, graft rejection, and delayed-type hypersensitivity
(DTH) reactions. They can induce autoimmune
and inflammatory reactions, and they have important
antiviral, antibacterial, antifungal, and antitumor activities.
IFN-beta2 has important immunomodulatory activity and poor antiviral
activity. It has also been called "B-cell
differentiation factor" because it stimulates mature B to differentiate
into Ig-secreting plasma cells. It also plays a role in early hematopoiesis and
may be an important autocrine growth factor for B cell malignancies
IFN-gamma is unrelated to the other IFNs
in either structure or function. Its biologic effects include enhancing cytotoxic T-cell and NK-cell activity, induction
of class II antigen expression on B cells, and other antigen-presenting cells,
and induction of IL-2 receptor expression on T cells. It
down-regulates collagen synthesis and inhibits IL-4-induced IgE synthesis.
·
Anergy
is the lack of an immunologic response to an antigen under circumstances in
which one would normally expect to see one. T-cell
anergy, for example, is demonstrated by the lack of reaction to
common delayed-type hypersensitivity recall antigens. Clinically this is seen
frequently in patients with miliary tuberculosis, Hodgkin's disease, or HIV
infection. B-cell anergy is failure
to develop a specific antibody response in a person who has been immunized with
antigens that are known to routinely stimulate antibody responses in other
individuals of the same species. Anergy may be temporary, as occurs during
measles infection, or of indeterminate duration, as in sarcoidosis, AIDS, and
certain disseminated malignancies and overwhelming infectious diseases,
including lepromatous leprosy.
·
Degranulation resulting from cross-linking of cell-bound IgE is called an anaphylactic reaction; degranulation caused by
activation of antigen nonspecific receptors like
those for C3a or C5a, which does not involve the IgE receptors,
is called an anaphylactoid reaction.
·
Humans also appear to have two major mast cell populations that are
identified by differences in neutral protease content of their cytoplasmic
granules. Both populations contain tryptase, but only one contains both
tryptase and chymase. The tryptase-only mast
cells (MCT) are located primarily at mucosal surfaces, whereas the tryptase- and chymase-positive mast cells (MCTC)
are located primarily in connective tissue, around blood vessels, and at
serosal surfaces. The factors responsible for human mast cell growth remain to
be clearly defined. Although human IL-3 appears to have some mast cell
growth-promoting activity, its effects are less well defined. Of interest is
that MCT mast cells, but not MCTC mast
cells, appear to be T lymphocyte-dependent.
This is suggested by a marked decrease in MCT
but not MCTC mast cell numbers in the tissues of patients with severe T-cell
immunodeficiency disorders.
·
IgG2 deficiency
sometimes accompanies IgA deficiency, and these patients are
particularly prone to infectious complications with encapsulated bacteria (such
as Streptococcus pneumoniae, or Haemophilus influenzae) because the principal
IgG antibody response against bacterial polysaccharide is usually IgG2.
·
CVID
is a heterogeneous group of disorders characterized by hypogammaglobulinemia (total IgG < 250
mg/dL and total Ig usually < 350 mg/dL), decreased ability to produce
antibody following antigenic challenge, and recurrent infections.
Patients with CVID
have an increased frequency of autoimmune disorders, including pernicious
anemia, Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, and
thyroiditis. GI disorders are common, including diarrhea, malabsorption, and
nodular lymphoid hyperplasia of the small intestine. Finally, there is an
increased incidence of malignancy, particularly of the lymphoreticular system
and the GI tract.
·
Elevation of the
total serum IgE level:
ü Atopic (allergic) diseases (allergic rhinitis, allergic asthma, allergic
bronchopulmonary aspergillosis)
ü Primary immunodeficiency disorders (Wiskott-Aldrich syndrome, Nezelhof's syndrome
[cellular immunodeficiency with IgE], selective IgA deficiency with concomitant
atopic disease, Job's syndrome)
ü Infections (parasitic; viral, including infectious mononucleosis and others; fungal,
including candidiasis and others)
ü Malignancies (Hodgkin's disease, bronchial carcinoma, IgE myeloma)
ü Dermatologic disorders (atopic dermatitis, bullous pemphigoid, eczema,
and others)
ü Acute GVHD
·
HAE is
transmitted in an AD pattern,
although sporadic cases do occur. The age of onset is variable, and the
diagnosis can be hindered by a predilection for nonlaryngeal sites, such as the
abdominal viscera.
Urticaria, although commonly seen in association
with other causes of angioedema, is not part of the HAE syndrome.
Pain, not pruritus, is typical of HAE lesions. If pruritus is
intense, it is likely that one is dealing with urticarial angioedema. Patients
typically have depressed serum C4 levels even when they are asymptomatic
between attacks.
Attenuated
androgen (i.e., stanazolol) therapy
dramatically decreases the severity and frequency of attacks. Androgens should
be tapered to the lowest dose that adequately controls disease activity in order
to minimize potential adverse effects such as virilization and hepatic
toxicity.
·
The gold standard for diagnosing food allergens is a double-blind,
placebo-controlled ingestion of the suspected food (DBPCFC).
To disguise the food's appearance, it is often desirable to put the food in
gelatin capsules.
·
Chinese restaurant
syndrome: It is a reaction to glutamate ingested as MSG (monosodium glutamate), a flavoring agent
commonly used in Chinese cooking. It occurs within 15-30 minutes of ingestion
and consists of a sensation of warmth and tightness on the face and anterior
chest. It is occasionally confused with angina pectoris but is benign and
requires no therapy except avoidance of foods cooked with MSG.
·
Corticosteroids on
circulating leukocytes: neutrophil numbers increase,
partly due to accelerated release from the bone marrow and partly due to the
decreased ability of neutrophils to migrate out of the circulation during
corticosteroid treatment. The numbers of circulating lymphocytes,
monocytes, and particularly eosinophils decreases. Overall, the total
white count is increased.
·
HLA compatibility of donor and recipient affects
graft outcome in both solid organ transplantation (such as kidney, heart, lung,
and liver) and BMT. For solid organs,
matching for the HLA-D or MHC type II antigens is more important than
matching at HLA-A or HLA-B, the MHC type I antigens, because MHC class II
molecules are involved in activating CD4 helper T cells that are needed for
both humoral and cell-mediated effector functions that attack the graft. HLA
incompatibility may lead to graft rejection of solid organ transplantation and
to GVHD in BMT.
ABO blood typing is critical in solid organ
transplants because ABO antigens are expressed on all tissue cells of the
transplanted organ, and because type O, type A, or type B recipients almost
always have preformed antibodies to these blood group antigens. Thus,
transplantation of solid organ grafts at a minimum requires compatibility at
ABO. However, ABO compatibility, oddly enough,
is not a requirement for bone marrow grafting because the donor graft will
thereafter supply all blood cells.
·
Certain medications, including isoniazid
used for tuberculosis, L-dopa used for Parkinson’s disease, and penicillamine
used for scleroderma, promote vitamin B6 (pyridoxine) deficiency by
reacting with a carbonyl group on 5pyridoxal
phosphate, which is a cofactor for a host of enzymes involved in
amino acid metabolism. Foods that contain vitamin B6 include legumes,
nuts, wheat bran, and meat. Vitamin B6 deficiency produces
seborrheic dermatitis, glossitis, stomatitis, and cheliosis (also seen in other
vitamin B deficiencies). A microcytic, hypochromic anemia may result from
the fact that the first enzyme in heme
synthesis (aminolevulinic synthetase) requires pyridoxal
phosphate as a cofactor. However, vitamin B6 is also necessary for the
conversion of homocysteine to cystathionine.
Consequently, a deficiency of this vitamin could produce an increased
risk of cardiovascular disease caused by the resultant hyperhomocystinemia.
·
The Confusion
Assessment Method (CAM) is highly sensitive and specific for
identifying delirium. One common misconception is that all delirious
patients are agitated. In fact, delirium is often associated with a decreased
level of consciousness, and patients can appear withdrawn or aloof, rather than
agitated, combative, or anxious. Another crucial diagnostic criterion is that
the patient’s mental state represents a clear, acute deviation from their
baseline status.
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