An especially elaborate and important type of innate antimicrobial enzymes defense is provided by a group of serum proteins that together make up the complement cascade pathway. This group comprises more than two dozen different liver-and macrophage-derived proteins, called complement factors or components, most of which normally circulate in the form of proenzymes that have latent protease activity. As a rule, each of the proteases becomes active when proteolytically cleaved and will then catalyze cleavage and activation of a different complement component. (more…)

The overlapping functions of cytokines largely reflect the properties of the cell surface receptors to which they bind. All cytokine receptors function as multiprotein complexes made up of two or more integral membrane polypeptides, called subunits (Figure 1 bellow). A typical subunit polypeptide has an extracellular domain that participates in cytokine binding, a transmembrane region, and an intracellular domain (also called a cytoplasmic tail gp41) involved in signal transduction the molecular events that transmit signals to the cell interior and induce specific cellular responses when the receptor binds its appropriate cytokine ligand. Some receptors (eg, EPO-R) function as homodimers of a single type of subunit; others (eg, GM-CSFR) function as heterodimers, and still others (eg, IL-2R) as heterotrimers. (more…)

Perhaps the most exciting recent advance in the cytokine signaling field has been the elucidation of the Jak/Stat pathway. The Janus kinase (Jak) family consists of four known enzymes (Jak1, Jak2, Jak3, and Tyk2), each of which associates specifically with the cytoplasmic tails of one or more cytokine receptor subunits. For example, IL-2R associates with both Jak1 and Jak3, which bind its α and γ subunits, respectively. Cytokine binding brings the receptor subunits together and allows the associated Jak proteins to phosphorylate and activate one another. The primary substrates of the activated Jaks are a family of transcription factors called the Stat (for signal transducers and activators of transcription) proteins. The Stat proteins contain SH2 domains and so are recruited to the vicinity of an activated receptor when its kinases become active. (more…)

The Ras-dependent pathway can be triggered by a variety of cytokine receptors, as well as by certain adhesion molecules and by many other surface receptors when they contact appropriate ligands. Signaling in this pathway can be initiated by cytosolic proteins called Src-family kinases, so named because they bear regions of sequence homology to the oncoprotein Src. These Src-like kinases contain specialized protein domains, termed SH2 domains (for Src-homology region 2), that enable them to bind other proteins containing phosphorylated tyrosine residues. When a cytokine receptor binds ligand, subunits of the receptor become phosphorylated and can immediately be bound by a Src-family kinase. (more…)

A few of the best known humoral effectors of innate immunity are listed in Table 1 bellow, along with the types of target molecules they recognize. Some are enzymes that can directly injure or kill microbial pathogens. An example is lysozyme, an endoglycosidase found in human saliva, mucus, tears, and other secretions, which attacks the protective cell wall encasing every bacterial cell. Lysozyme acts by digesting the peptidoglycan meshwork formed by long carbohydrate chains of alternating N-acetylmuramic acid and N-acetylglucosamine residues, crosslinked covalently by short oligopeptide sidechains which is a major constituent of all bacterial cell walls but is not found in mammalian tissues. (more…)

The body’s innate resistance to many pathogens is provided by enzymes and other proteins in the blood and tissue fluids. These proteins are the effectors (ie, the active agents) of humoral innate immunity, and they have features in common with one another that are also characteristics of the innate immune system as a whole. First, these proteins are continually expressed throughout life, regardless of whether or not their protective effects are needed at a given moment. Second, although many of these proteins can be produced in higher quantities in times of need, their intrinsic properties (eg, substrate specificity and ige binding affinity) never change: The characteristics of these proteins have been shaped by evolution, are genetically determined, and are fixed at birth, so that they do not vary during an individual’s lifetime. (more…)

Although it is commonly imagined that hematopoiesis takes place in a liquid environment resembling the blood, with progenitors responding mainly to soluble hormone-like cytokines, this is in fact not the case at all. It is much more accurate to think of the bone marrow as a solid tissue in which different types of hematopoietic cells develop in physically different locations. These microenvironments are visible in histologic sections of bone marrow, which reveal a patchwork of microscopic foci, each devoted to the production of a particular cell type (Figure bellow). The bone marrow microenvironment is set up and maintained by bone marrow stromal cells. Within each microenvironment, contact of cells with one another or with proteins and other substances that make up the extracellular matrix (ECM) greatly facilitates cell division and differentiation. (more…)

The final stage of the disease process (although it may not be the final stage of the infection) is the actual production of disease. Many microorganisms live in or on the body without causing disease. These organisms are called commensal organisms and may be beneficial to the host: the production of lactic and lactobacilli proprionic acidophilus in the vagina inhibits the growth of many other bacteria and many commensal organisms compete with pathogens for ‘living space’ in the gut. Microbial pathogens differ in that they cause dis- ease by one or more mechanisms like picture bellow. These include the following: (more…)

Routes by which infectious organisms gain entry into the body include the skin, respiratory tract, gastro-intestinal (GI) tract and GU tract. There are fundamentally two ways in which infectious agents cross the physical and chemical barriers: either they are able to penetrate the intact barriers at one or more anatomical sites, or the physical barriers are damaged and breached, allowing entry of the organism.

Bellow are some possibles pathogens entry into human body:

Penetration of intact skin or mucosa

• Skin. Few organisms are able to penetrate intact skin. However, some parasites (e.g. hookworm) or their larvae (e.g. schistosoma) can do this. Other agents, such as wart viruses, set up infection in the skin and do not enter further into the body.

• Mucosa. Mucosa, being softer and damper than skin, are much more frequent sites of entry and all intact mucosa can be penetrated by some organisms. Examples are shown in table bellow. Pathogens can cross epithelia by passing through epithelial cells, as in the case of the meningococcus (a bacteria causing meningitis), or by passing between the epithelial cells, seen with Haemophilus influenzae.

Mucosal Sites of Entry for Pathogens

Penetration of damaged skin or mucosa

There are many ways in which skin or mucosa can be damaged, allowing entry of infectious organisms that could not cross intact skin or mucosa. Damage to skin is a particularly important route of infection and can occur in a number of ways:

• Burns. Burns, especially severe ones, pose a major risk for infection, particularly with Staphylococcus, Streptococcus, Pseudomonas and Clostridium tetanus.

• Cuts and wounds. These can allow entry of similar organisms to those seen after burns.

• Insect bites. Numerous infections pathogenesis are transmitted via insect bites. These include malaria, typhus and plague.

• Animal bites. Animal bites can provide direct transmission of infection, such as in rabies. Because they cause significant damage to the skin, bites can allow the entry of the same environmental pathogens as burns, cuts and wounds (see above).

• Human behaviour. Various aspects of uniquely human behaviour can result in the skin being penetrated. Sharing of syringes by intravenous (IV) drug users exposes them to risk of hepatitis and human immunodeficiency virus (HIV). A number of viral infections (hepatitis, HIV) have been transmitted by blood transfusion and blood products (e.g. factor VIII for haemophiliacs) before appropriate screening procedures were developed. Transplantation has also resulted in transmission of infection before the introduction of appropriate donor screening.

Damage to mucosa may not increase the likelihood of infection to the same extent as damage to the skin. However, physical or chemical damage may allow entry of some organisms (e.g. smoking increases the risk of respiratory bacterial infections or respiratory allergies). Furthermore, infection of the mucosa with a virus may cause damage and facilitate the entry of bacterial pathogens spread.

There are several pathogen types that can cause disease include many groups of single-celled microorganisms and larger multicellular parasites. Viruses, bacteria, some yeasts, and protozoan parasites are examples of single- celled pathogens. Fungi and helminths (parasitic worms) are the major multi-cellular pathogens. These pathogens come from very different parts of the biological kingdom and vary considerably in many aspects. Pathogens differ enormously in their size. They also have very different lifestyles and cause disease in a variety of ways like bellow:

Poliovirus (Viruses)

Size: 20–400nm
Habitat: Intracellular: pharynx, intestine, nervous system
Mode of multiplication: Intracellular synthesis of viral components
Multiplication rate (doubling time): <1 hour

Poxvirus (Viruses)

Size: 20–400nm
Habitat: Intracellular: upper respiratory tract, lymph nodes, skin
Mode of multiplication: Intracellular synthesis of viral components
Multiplication rate (doubling time): <1 hour

Streptococcus pyogenes (Bacteria)

Size: 1–5µm
Habitat: Extracellular: pharynx
Mode of multiplication: Cell fission
Multiplication rate (doubling time): 3 hours

Mycobacterium leprae (Bacteria)

Size: 1–5µm
Habitat: Intracellular: macrophages, endothelial cells, Schwann cells
Mode of multiplication: Cell fission
Multiplication rate (doubling time): 2 weeks

Candida albicans (Fungi)

Size: 2–20µm
Habitat: Extracellular: mucosal surfaces
Mode of multiplication: Asexual budding
Multiplication rate (doubling time): Hours

Histoplasma capsulatum (Fungi)

Size: 2–20µm
Habitat: Intracellular: macrophages
Mode of multiplication: Asexual budding
Multiplication rate (doubling time): Hours

Trypanosomes (Protozoan parasites)

Size: 1–50mm
Habitat: Extracellular: bloodstream
Mode of multiplication: Binary fission
Multiplication rate (doubling time): 6.5 hours

Plasmodium (Protozoan parasites)

Size: 1–50mm
Habitat: Intracellular: red blood cells, hepatocytes
Mode of multiplication: Asexually in hepatocytes (cell fission)
Multiplication rate (doubling time): 8 hours

Ascaris lumbricoides (Metazoan parasites worms)

Size: 3mm to 7m
Habitat: Intestine
Mode of multiplication: Lays eggs
Multiplication rate (doubling time): 200000 eggs/day

Taenia solium tapeworm (Metazoan parasites worms)

Size: 3mm to 7m
Habitat: Gut
Mode of multiplication: Releases body segments containing eggs
Multiplication rate (doubling time): 800000 eggs/day

Size of pathogens

One feature of the range of pathogenic organisms listed above is the enormous variation in size. Viruses are the smallest infectious organisms, being 20–400 nm in size. At the other end of the scale some parasitic worms, such as the tapeworm, can be up to 7 m (20 ft) in length. This represents a difference in scale of a factor of 10e9 . To put that into some sort of perspective, if a virus were the size of a tennis ball, a fully developed tape- worm would reach from London to Los Angeles. It does not stretch the imagination too far to appreciate that the problems posed to the immune system by these two organisms would require very different solutions.

Stages of disease production by pathogens

Size is not the only way in which infectious organisms vary. They also vary enormously with respect to how they enter and live within the body and actually cause disease. Infection and disease production by pathogenic organisms can be divided into four stages:

1. Invasion.
2. Multiplication.
3. Spread.
4. Production of disease (pathogenesis).

Although infection usually involves all of these steps, there are many exceptions in terms of both the steps involved and their order. Some pathogens do not spread significantly or even technically gain entry to the body. Organisms may replicate locally before spreading or may spread through the body before beginning significant replication. Pathogens show considerable variation at each of these stages of infection, as will be described below.