книги студ / color atlas of physiology 5th ed[1]. (a. despopoulos et al, thieme 2003)

Iron Metabolism and Erythropoiesis

Roughly 2/3 of the body’s iron pool (ca. 2 g in women and 5 g in men) is bound to hemoglobin (Hb). About 1/4 exists as stored iron (ferritin, hemosiderin), the rest as functional iron (myoglobin, iron-containing enzymes). Iron losses from the body amount to about 1 mg/day in men and up to 2 mg/day in women due to menstruation, birth, and pregnancy. Iron absorption occurs mainly in the duodenum and varies according to need. The absorption of iron supplied by the diet usually amounts to about 3 to 15% in healthy individuals, but can increase to over 25% in individuals with iron deficiency (!A1). A minimum daily iron intake of at least 10–20 mg/day is therefore recommended (women ! children ! men).

Iron absorption (!A2). Fe(II) supplied by the diet (hemoglobin, myoglobin found chiefly in meat and fish) is absorbed relatively efficiently as a heme-Fe(II) upon protein cleavage. With the aid of heme oxygenase, Fe in mucosal cells cleaves from heme and oxidizes to Fe(III). The triferric form either remains in the mucosa as a ferritin-Fe(III) complex and returns to the lumen during cell turnover or enters the bloodstream. Non-heme-Fe can only be absorbed as Fe2+. Therefore, non-heme Fe(III) must first be reduced to Fe2+ by ferrireductase (FR; !A2) and ascorbate on the surface of the luminal mucosa (!A2). Fe2+ is probably absorbed through secondary active transport via an Fe2+-H+ symport carrier (DCT1) (competition with Mn2+, Co2+, Cd2+, etc.). A low chymous pH is important since it (a) increases the H+ gradient that drives Fe2+ via DCT1 into the cell and (b) frees dietary iron from complexes. The absorption of iron into the bloodstream is regulated by the intestinal mucosa. When an iron deficiency exists, aconitase (an iron-regu- lating protein) in the cytosol binds with fer- ritin-mRNA, thereby inhibiting mucosal ferritin translation. As a result, larger quantities of absorbed Fe(II) can enter the bloodstream. Fe(II) in the blood is oxidized to Fe(III) by ceruloplasmin (and copper). It then binds to apotransferrin, a protein responsible for iron transport in plasma (!A2, 3). Transferrin

(= apotransferrin loaded with 2 Fe(III)), is taken up by endocytosis into erythroblasts and cells of the liver, placenta, etc. with the aid of

transferrin receptors. Once iron has been released to the target cells, apotransferrin again becomes available for uptake of iron from the intestine and macrophages (see below).

Iron storage and recycling (!A3). Ferritin, one of the chief forms in which iron is stored in the body, occurs mainly in the intestinal mucosa, liver, bone marrow, red blood cells, and plasma. It contains binding pockets for up to 4500 Fe3+ ions and provides rapidly available stores of iron (ca. 600 mg), whereas iron mobilization from hemosiderin is much slower (250 mg Fe in macrophages of the liver and bone marrow). Hb-Fe and heme-Fe released from malformed erythroblasts (so-called inefficient erythropoiesis) and hemolyzed red blood cells bind to haptoglobin and hemopexin, respectively. They are then engulfed by macrophages in the bone marrow or in the liver and spleen, respectively, resulting in 97% iron recycling (!A3).

An iron deficiency inhibits Hb synthesis, leading to hypochromic microcytic anemia: MCH "26 pg, MCV "70 fL, Hb "110 g/L. The primary causes are:

blood loss (most common cause); 0.5 mg Fe are lost with each mL of blood;

insufficient iron intake or absorption;

increased iron requirement due to growth, pregnancy, breast-feeding, etc.;

decreased iron recycling (due to chronic infection);

apotransferrin defect (rare cause).

Iron overload most commonly damages the liver, pancreas and myocardium (hemochromatosis). If the iron supply bypasses the intestinal tract (iron injection), the transferrin capacity can be exceeded and the resulting quantities of free iron can induce iron poisoning.

B12 vitamin (cobalamins) and folic acid are also required for erythropoiesis (!B). Deficiencies lead to hyperchromic anemia (decreased RCC, increased MCH). The main causes are lack of intrinsic factor (required for cobalamin resorption) and decreased folic acid absorption due to malabsorption (see also p. 260) or an extremely unbalanced diet. Because of the large stores available, decreased cobalamin absorption does not lead to symptoms of deficiency until many years later, whereas folic acid deficiency leads to symptoms within a few months.

A.Iron intake and metabolism

1Iron intake

Normal Fe intake: 10–20 mg/day

5–10 mg/day

Fe

Fe absorption:

3–15% of HCI Fe intake

Liver

Non-absorbed Fe in feces:

Normally 85–97% of intake

3 Fe storage and Fe recycling

2 Fe absorption

Transferrin

Fe

Erythrocytes

B. Folic acid and vitamin B12 (cobalamins)

Ileum

NADP NADPH +H+

Dihydrofolate reductase

DNA synthesis

Bone marrow

Immune System

Fundamental Principles

The body has nonspecific (innate) immune defenses linked with specific (acquired) immune defenses that counteract bacteria, viruses, fungi, parasites and foreign (non-self) macromolecules. They all function as antigens, i.e., substances that stimulate the specific immune system, resulting in the activation of an- tigen-specific T lymphocytes (T cells) and B lymphocytes (B cells). In the process, B lymphocytes differentiate into plasma cells that secrete antigen-specific antibodies (immunoglobulins, Ig) (!C). Ig function to neutralize and opsonize antigens and to activate the complement system (!p. 96). These mechanisms ensure that the respective antigen is specifically recognized, then eliminated by relatively nonspecific means. Some of the T and B cells have an immunologic memory.

Precursor lymphocytes without an antigenbinding receptor are preprocessed within the thymus (T) or bone marrow (B). These organs produce up to 108 monospecific T or B cells, each of which is directed against a specific antigen. Naive T and B cells which have not previously encountered antigen circulate through the body (blood !peripheral lymphatic tissue !lymph !blood) and undergo clonal expansion and selection after contact with its specific antigen (usually in lymphatic tissue). The lymphocyte then begins to divide rapidly, producing numerous monospecific daughter cells. The progeny differentiates into plasma cells or “armed” T cells that initiate the elimination of the antigen.

Clonal deletion is a mechanism for eliminating lymphocytes with receptors directed against autologous (self) tissue. After first contact with their specific self-antigen, these lymphocytes are eliminated during the early stages of development in the thymus or bone marrow. Clonal deletion results in central immunologic tolerance. The ability of the immune system to distinguish between endogenous and foreign antigens is called self/nonself recognition. This occurs around the time of birth. All substances encountered by that time are recognized as endogenous (self); others are identified as foreign (nonself). The inability to distinguish self from nonself results in autoimmune disease.

At first contact with a virus (e.g., measles virus), the nonspecific immune system usually cannot prevent the viral proliferation and the development of the measles. The specific immune system, with its T-killer cells (!B2) and Ig (first IgM, then IgG; !C3), responds slowly: primary immune response or sensitization. Once activated, it can eliminate the pathogen, i.e., the individual recovers from the measles.

Secondary immune response: When infected a second time, specific IgG is produced much more rapidly. The virus is quickly eliminated, and the disease does not develop a second time. This type of protection against infectious disease is called immunity. It can be achieved by vaccinating the individual with a specific antigen (active immunization). Passive immunization can be achieved by administering ready-made Ig (immune serum).

Nonspecific Immunity

Lysozyme and complement factors dissolved in plasma (!A1) as well as natural killer cells (NK cells) and phagocytes, especially neutrophils and macrophages that arise from monocytes that migrate into the tissues (!A2) play an important role in nonspecific immunity. Neutrophils, monocytes, and eosinophils circulate throughout the body. They have chemokine receptors (e.g., CXCR1 and 2 for IL- 8) and are attracted by various chemokines (e.g., IL-8) to the sites where microorganisms have invaded (chemotaxis). These cells are able to migrate. With the aid of selectins, they dock onto the endothelium (margination), penetrate the endothelium (diapedesis), and engulf and damage the microorganism with the aid of lysozyme, oxidants such as H2O2, oxygen radicals (O2–, OH·, 1O2), and nitric oxide (NO). This is followed by digestion (lysis) of the microorganism with the aid of lysosomal enzymes. If the antigen (parasitic worm, etc.) is too large for digestion, other substances involved in nonspecific immunity (e.g., proteases and cytotoxic proteins) are also exocytosed by these cells.

Reducing enzymes such as catalase and superoxide dismutase usually keep the oxidant concentration low. This is often discontinued, especially when macrophages are activated (!below and B3), to fully exploit the bactericidal effect of the oxidants. However,