Immunology

·         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.

·         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.

·         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.