Imunoglobulina A - IgA

Immunoglobulin A (IgA) is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined; between three and five grams are secreted into the intestinal lumen each day. This accumulates up to 15% of the total immunoglobulin produced in the entire body. IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory IgA (sIgA). In its secretory form, IgA is the main immunoglobulin found in mucous secretions, including tears, saliva, colostrum and secretions from the genitourinary tract, gastrointestinal tract, prostate and respiratory epithelium. It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes, thus sIgA can survive in the harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins. IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α. Pathology[edit source | editbeta]Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant immunodeficiency. Neisseria gonorrhœae (which causes gonorrhea), Streptococcus pneumoniae, and Haemophilus influenzae type B all release a protease which destroys IgA. IgA nephropathy is caused by IgA deposits in the kidneys. It is not yet known why IgA deposits occur in this chronic disease. Some theories suggest an abnormality of the immune system results in these deposits. Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies. Henoch–Schönlein purpura (HSP) is a systemic disorder caused by deposits of IgA and compliment component 3 (C3) in the small vessels. HSP occurs usually in small children and involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates.

Tacrolimus

Tacrolimus (also FK-506 or fujimycin, trade names Prograf, Advagraf, Protopic) is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection.

It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, and the skin condition vitiligo.

It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.
It reduces interleukin-2 (IL-2) production by T-cells. Mechanism of action Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT. In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.

Gene Rh D

Rh blood group, D antigen also known as Rh polypeptide 1 (RhPI) or cluster of differentiation 240D (CD240D) is a protein that in humans is encoded by the RHD gene.

The RHD gene codes for the RhD erythrocyte membrane protein that is the Rh factor antigen of the Rh blood group system.
RHD has sequence similarity to RHCE, RhAG, RhBG, and RhCG and these five genes constitute the Rh family. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE protein subunits.
RhAG is a functional ammonia transporter and is required for normal cell surface expression of RhD and
RhCE.

Patients who lack RhD/RhCE/RhAG on the surface of their erythrocytes have hemolytic anemia.

Antibodies to the RhD protein can cause Rh disease.

Teste de Coombs

The Direct Coombs test is used to test for autoimmune hemolytic anemia; i.e., a condition of a low count of red blood cells (aka RBCs) caused by immune system lysis or breaking of RBC membranes causing RBC destruction.

In certain diseases or conditions an individual's blood may contain IgG antibodies that can specifically bind to antigens on the RBC surface membrane, and their circulating RBCs can become coated with IgG alloantibodies and/or IgG autoantibodies. Complement proteins may subsequently bind to the bound antibodies and cause RBC destruction.

The direct Coombs test is used to detect these antibodies or complement proteins that are bound to the surface of red blood cells; a blood sample is taken and the RBCs are washed (removing the patient's own plasma) and then incubated with antihuman globulin (also known as "Coombs reagent"). If this produces agglutination of RBCs, the direct Coombs test is positive, a visual indication that antibodies (and/or complement proteins) are bound to the surface of red blood cells.

The indirect Coombs test is used in prenatal testing of pregnant women, and in testing blood prior to a blood transfusion. It detects antibodies against RBCs that are present unbound in the patient's serum. In this case, serum is extracted from the blood sample taken from the patient. Then, the serum is incubated with RBCs of known antigenicity; that is, RBCs with known reference values from other patient blood samples. If agglutination occurs, the indirect Coombs test is positive.

IgG

Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled, polyvalent, IgG (immunoglobulin (antibody) G) extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months. It is mainly used as treatment in three major categories:

• Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels.
• Autoimmune diseases, e.g. immune thrombocytopenia, and inflammatory diseases, e.g. Kawasaki disease.
• Acute infections.

IVIG use[edit source | editbeta]

IVIG is given as a plasma protein replacement therapy (IgG) for immune deficient patients who have decreased or abolished antibody production capabilities. In these immune deficient patients, IVIG is administered to maintain adequate antibody levels to prevent infections and confers a passive immunity. Treatment is given every 3–4 weeks. In the case of patients with autoimmune disease, IVIG is administered at a high dose (generally 1-2 grams IVIG per kg body weight) to attempt to decrease the severity of the autoimmune diseases such as dermatomyositis. Currently, IVIg is being increasingly used off-label in a number of pathological conditions; the increasing world-wide usage of IVIg may lead to shortages of this beneficial drug.

IVIG is useful in some acute infection cases such as pediatric HIV infection as well as autoimmune, such as Guillain–Barré syndrome.^[1]

As asthma treatment[edit source | editbeta]

Asthma is a condition which can have many causes. In patients with both immune abnormalities and an infection causing asthma, the triggering infection could be eliminated with IVIG therapy.^[2] However, most asthma patients have a normal immune system and their asthma is the result of lower airway inflammation which can be managed in the context of a healthy immune system.^[2][3] Despite popularity of use, IVIG is not recommended for recurrent asthma infections unless the patient presents an impaired response to vaccine immunizations or natural infections.^[2][3]

Mechanism of action[edit source | editbeta]

The precise mechanism by which IVIG suppresses harmful inflammation has not been definitively established but is believed to involve the inhibitory Fc receptor.^[4][5] However, the actual primary target(s) of IVIG in autoimmune disease are still unclear. IVIG may work via a multi-step model where the injected IVIG first forms a type of immune complex in the patient.^[6] Once these immune complexes are formed, they interact with activating Fc receptors on dendritic cells^[7] which then mediate anti-inflammatory effects helping to reduce the severity of the autoimmune disease or inflammatory state.

Additionally, the donor antibody may bind directly with the abnormal host antibody, stimulating its removal. Alternatively, the massive quantity of antibody may stimulate the host's complement system, leading to enhanced removal of all antibodies, including the harmful ones. IVIG also blocks the antibody receptors on immune cells (macrophages), leading to decreased damage by these cells, or regulation of macrophage phagocytosis.

IVIG may also regulate the immune response by reacting with a number of membrane receptors on T cells, B cells, and monocytes that are pertinent to autoreactivity and induction of tolerance to self.^[8]

A recent report stated that IVIG application to activated T cells leads to their decreased ability to engage microglia. As a result of IVIG treatment of T cells, the findings showed reduced levels of tumor necrosis factor-alpha and interleukin-10 in T cell-microglia co-culture. The results add to the understanding of how IVIG may affect inflammation of the central nervous system in autoimmune inflammatory diseases.^[9]

IVIG notes[edit source | editbeta]

• IVIG is an infusion of IgG antibodies only. Therefore, peripheral tissues that are defended mainly by IgA antibodies, such as the eyes, lungs, gut and urinary tract are not fully protected by the IVIG treatment.
• X-linked agammaglobulinemia patients are immune to the most dangerous adverse effect, anaphylactic shock, as they do not have the antibodies to react against the treatment. Anaphylactic shock has a higher chance to occur in IgA deficient patients which do have other antibody types.
• In case of recurring side effects, it is recommended to slow the pace of the IVIG administration and to reduce the dosage. It is also advisable to change IVIG brand, as some people react against a specific brand.
• If the patient is diabetic, he should take into consideration the medium in which the antibodies are solubilized in the IVIG treatment, as some brand solubilize antibodies with high concentrated sugars(such as sucrose and maltose).
• U.S. Food and Drug Administration (FDA) guidelines for IVIG state the product should be:
  • Prepared out of at least 1,000 different human donors.
  • All four IgG subgroups (1-4) should be present.
  • The IgG should maintain biological activity and lifetime of at least 21 days.
  • Does not contain samples which are HIV, hepatitis B, hepatitis C positive.
  • Screened and treated in a manner that destroys viruses.
• IVIG is also considered a modulator of the immune system and was shown to be beneficial in treating numerous autoimmune diseases such as relapsing, myasthenia gravis, pemphigus, polymyositis(PM), dermatomyositis (DM), Wegener's granulomatosis (WG), Churg-Strauss syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP) and more.
• IVIG can be given to pregnant women.
• IVIG is also used as a treatment for unexplained recurring miscarriages. The effectiveness of the therapy is controversial.
• IVIG cost is stable but over $75/g. ($15,000 for a 100 kg (220 lbs) person at 2g/kg)

IVIG dose[edit source | editbeta]

Dosage of IVIG is dependent on indication.

For primary immune dysfunction 100 to 400 mg/kg of body weight every 3 to 4 weeks is implemented. However that is just a starting dose. The dose needs to be adjusted on the needs of the patient. The therapeutic dose is the one that prevents serious infections and prevents the patient from getting more infections than the general population.

For neurological and autoimmune diseases 2 grams per kilogram of body weight is implemented for three to six months over a five day course once a month. Then maintenance therapy of 100 to 400 mg/kg of body weight every 3 to 4 weeks follows.

FDA-approved indications[edit source | editbeta]

• Allogeneic bone marrow transplant
• Chronic lymphocytic leukemia
• Common variable immunodeficiency (CVID) a group of approximately 150 primary immunodeficiencies (PIDs), which have a common set of features (including hypogammaglobulinemia) but which have different underlying causes
• Idiopathic thrombocytopenic purpura
• Pediatric HIV
• Primary immunodeficiencies
• Kawasaki disease
• Chronic inflammatory demyelinating polyneuropathy (CIDP). Only the "Gamunex" brand manufactured by Talecris is approved for CIDP (in 2008), under the U.S. Orphan Drug law provisions
• Kidney transplant with a high antibody recipient or with an ABO incompatible donor

In 2004 the FDA approved the Cedars-Sinai IVIG Protocol which has been 90-95% successful in removing antibodies from the blood of kidney transplant recipients so that they can accept a living donor kidney from any healthy donor no matter blood type (ABO incompatible) or tissue match.