Professional Documents
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Complement System
Zaahira Gani, Cambridge, UK
Classical Pathway
This pathway involves complement components C1, C2 and C4. The pathway is
triggered byantibody-antigen complexes binding to C1, which itself has three
subcomponents C1q, C1r andC1s. The pathway forms a C3 convertase, C4b2a,
which splits C3 into two fragments; the large fragment, C3b, can covalently attach
to the surface of microbial pathogens and opsonise them; the small fragment, C3a,
activates mast cells, causing the release of vasoactive mediators such as histamine.
Alternative Pathway
This pathway involves various factors, B, D, H & I, which interact with each other,
and with C3b, to form a C3 convertase, C3bBb, that can activate more C3, hence the
pathway is sometimes called ‘the amplification loop’. Activation of the loop is
promoted in the presence of bacterial and fungal cell walls, but is inhibited by
molecules on the surface of normal mammalian cells.
Mannose-binding Lectin Pathway
This pathway is activated by the binding of mannose-binding lectin (MBL) to
mannose residues on the pathogen surface. This in turn activates the
MBL-associated serine proteases, MASP-1and MASP-2, which activate C4 and C2, to
form the C3 convertase, C4b2a.
Lytic Pathway
This pathway is initiated by the splitting of C5, and attachment of C5b to a
target. C6, C7, C8 andC9 unite with C5b, and this membrane-attack
complex (MAC), when inserted into the outer membrane of some bacteria, can
contribute to their death by lysis. Red cells which have antibody bound to the cell
surface can also activate the classical and lytic pathways, and become susceptible
to lysis.
Complement Disease
Deficiency
I.Immediate
II.Cytotoxic
III.Immune complex
IV.Cell-mediated
Type I: Immediate Hypersensitivity (Anaphylactic Reaction) These allergic reactions are systemic or
localized, as in allergic dermatitis (e.g., hives, wheal and erythema reactions). The reaction is the result of an
antigen cross-linking with membrane-bound IgE antibody of a mast cell or basophil. Histamine, serotonin,
bradykinin, and lipid mediators (e.g., platelet activating factor, prostaglandins, and leukotrienes) are
released during the anaphylactic reaction. These released substances have the potential to cause tissue
damage.
In a cytotoxic reaction, the antibody reacts directly with the antigen that is bound to the cell membrane to
induce cell lysis through complement activation. These antigens may be intrinsic or “self” as in autoimmune
reactions or extrinsic or “non-self.” Cytotoxic reactions are mediated by IgG and IgM. Examples of cytotoxic
reaction are the Rh incompatibility of a newborn, blood transfusion reactions, and autoimmune diseases like
Pemphigus Vulgaris, Bullous Pemphigoid, autoimmune hemolytic anemia and Goodpasture's syndrome to
name a few.
IgG and IgM bind antigen, forming antigen-antibody (immune) complexes. These activate complement, which
results in PMN chemotaxis and activation. PMNs then release tissue damaging enzymes. Tissue damage
present in autoimmune diseases (e.g., systemic lupus erythematosus), and chronic infectious diseases (e.g.,
leprosy) can be attributed, in part, to immune complex reactions.
Immunodeficiency
Immunodeficiency disorders result in a full or partial impairment of the
immune system. Primary immunodeficiencies are the result of genetic
defects, and secondary immunodeficiencies are caused by environmental
factors, such as HIV/AIDS or malnutrition. This briefing explains the two
different types of immunodeficiencies and how they are currently treated. It
also discusses the future research required in this field to develop better
curative treatments for these immune disorders.
Key points
● Immunodeficiency disorders result in partial or full impairment of the immune
system, leaving the patient unable to effectively resolve infections or disease.
● Immunodeficiency disorders can either be primary or secondary in nature. There
are over 300 forms of primary immunodeficiency and, although rare, the condition
can be life threatening.
● Secondary immunodeficiencies are the result of disease or other environmental
factors weakening the immune system.
● Although affecting fewer patients than other classes of immune illness,
immunodeficiency patients may require expensive definitive therapy (e.g. bone
marrow transplant), or may remain lifelong patients with complex care needs, and
the cost-burden on the NHS is significant.
● Immunological research provides hope of improved curative therapies through the
development of new technologies. Continued and increased investment is critical to
ensure these potential advances are realised.
Introduction
In healthy individuals the immune response comprises two phases. The first line of
defence is the innate system, made up of specialised cells that provide a rapid
response that is not tailored to the specific microbe that has infiltrated the body.
Sometimes this can clear the infection alone but usually the innate response will
contain the infection long enough for the adaptive immune system to activate. The
adaptive response is the second line of defence and takes several days to assemble.
The response is specific to the microbe and leaves a lasting immune memory,
which makes the response to future reinfection more efficient (see here for more
information). In a person with an immunodeficiency disorder, one or more
components of either the adaptive or innate immune response is impaired,
resulting in the body being unable to effectively resolve infections or disease. This
leaves immunodeficient individuals at high risk of recurrent infection, and
vulnerable to conditions that would not usually be of concern to otherwise healthy
individuals.
There are two types of immunodeficiency disorder:
1. Primary immunodeficiency (PID) – inherited immune disorders resulting from
genetic mutations, usually present at birth and diagnosed in childhood.
2. Secondary immunodeficiency (SID) – acquired immunodeficiency as a result of
disease or environmental factors, such as HIV, malnutrition, or medical treatment
(e.g. chemotherapy).
B cell immunodeficiencies (adaptive) – B cells are one of two key cell types of the
adaptive immune system. Their main role is to produce antibodies, which are
proteins that attach to microbes, making it easier for other immune cells to detect
and kill them. Mutations in the genes that control B cells can result in the loss of
antibody production. These patients are at risk of severe recurrent bacterial
infections.
T cell immunodeficiencies (adaptive) – T cells are the second of two key cell types of
the adaptive immune system. One role of the T cell is to activate the B cell and pass
on details of the microbe’s identity, so that the B cell can produce the correct
antibodies. Some T cells are also directly involved in microbe killing. T cells also
provide signals that activate other cells of the immune system. Mutations in the
genes that control T cells can result in fewer T cells or ones that do not function
properly. This can lead to their killing ability being disrupted, and can often cause
problems with B cell function too. Therefore, T cell immunodeficiencies can often
lead to combined immunodeficiencies (CIDs), where both T and B cell function is
defective. Some forms of CIDs are more severe than others.
Severe combined immune deficiencies (SCID) (adaptive) – SCID disorders are very rare
but extremely serious. In SCID patients there is often a complete lack of T cells and
variable numbers of B cells, resulting in little-to-no immune function, so even a
minor infection can be deadly. SCID patients are usually diagnosed in the first year
of life with symptoms such as recurrent infections and failure to thrive.
Phagocyte disorders (innate) - phagocytes include many white blood cells of the
innate immune system, and these cells patrol the body eating any pathogens they
come across. Mutations typically affect the ability of certain phagocytes to eat and
destroy pathogens effectively. These patients have largely functional immune
systems but certain bacterial and fungal infections can cause very serious harm or
death.
Complement defects (innate) – complement defects are some of the rarest of all the
PIDs, and account for less than 1% of diagnosed cases. Complement is the name
given to specific proteins in the blood that help immune cells clear infection. Some
deficiencies in the complement system can result in the development of
autoimmune conditions such as systemic lupus erythematosus and rheumatoid
arthritis (please see our autoimmune briefing for more information). Patients who
lack certain complement proteins are highly susceptible to meningitis.
Treatments and outcomes
The prognosis of patients with PIDs is extremely variable and depends on the
condition. Most SCID patients will die before the age of 1 without prompt
treatment, although 95% of those that receive a bone marrow transplant (BMT)
before 3 months of age will survive.iii Forty-three states in the USA now screen for
SCID disorders at birth, but this is not yet routinely available in the UK.iv,v A famous
SCID disorder patient was David Vetter, known as “the boy in the bubble”, who from
birth was isolated into a sterile environment while his family searched for a suitable
bone marrow match. He died at the age of 12 from Burkitt’s lymphoma probably
triggered by the Epstein-Barr virus, which lay dormant and undetected in the
transplanted bone marrow he recieved. BMT is the preferred long-term treatment
option for CIDs/SCIDs and some phagocyte disorders, although some SCIDs are
now routinely treated with gene therapy. Supportive therapy for all PID conditions
involves routine preventative use of antibiotics and antifungals. B cell disorders can
also be managed with immunoglobulin (antibody) replacement therapy, where
immunoglobulin G is purified from the blood plasma of healthy donors and infused
into the patient.vi
Key vaccines are recommended for patients with innate deficiencies, but live
vaccines (such as MMR) must be avoided for CID/SCID patients. It is therefore
crucial that there is enough vaccine coverage in their local communities to generate
“herd immunity”, where vaccine rates are at 95% or above ensuring resistance to
disease transmission exists across the whole community, even for the few patients
who cannot be vaccinated (please see out vaccine briefing for more information).
For many SID disorders treatment of the primary condition will lead to resolution of
the immunodeficiency. This is of limited use in chronic conditions such as organ
transplantation or HIV where the emphasis is on managing the condition to
minimise immunodeficiency. With advances in medical science the prognosis for
these patients is now much improved. There is evidence to suggest that more
patients with HIV now die from toxicity associated with the anti-retroviral
therapy than the disease itself, and that managing this is the next big challenge.ix
Comorbidities, such as secondary infections, are a major cause for concern and
account for a high proportion of deaths in SID patients. As with PIDs, high
community vaccine rates and herd immunity are vital to prevent transmission of
common diseases to immunocompromised individuals, who cannot be vaccinated.
Autoimmune disorders
An autoimmune disorder occurs when the body's immune system attacks and destroys healthy
body tissue by mistake. There are more than 80 types of autoimmune disorders.
Causes
The blood cells in the body's immune system help protect against harmful substances. Examples
include bacteria, viruses, toxins, cancer cells, and blood and tissue from outside the body. These
substances contain antigens. The immune system produces antibodies against these antigens that
enable it to destroy these harmful substances.
When you have an autoimmune disorder, your immune system does not distinguish between
healthy tissue and antigens. As a result, the body sets off a reaction that destroys normal tissues.
The exact cause of autoimmune disorders is unknown. One theory is that some microorganisms
(such as bacteria or viruses) or drugs may trigger changes that confuse the immune system. This
may happen more often in people who have genes that make them more prone to autoimmune
disorders.
An autoimmune disorder may result in:
● The destruction of body tissue
● Abnormal growth of an organ
● Changes in organ function
An autoimmune disorder may affect one or more organ or tissue types. Areas often affected by
autoimmune disorders include:
● Blood vessels
● Connective tissues
● Endocrine glands such as the thyroid or pancreas
● Joints
● Muscles
● Red blood cells
● Skin
A person may have more than one autoimmune disorder at the same time. Common autoimmune
disorders include:
● Addison disease
● Celiac disease - sprue (gluten-sensitive enteropathy)
● Dermatomyositis
● Graves disease
● Hashimoto thyroiditis
● Multiple sclerosis
● Myasthenia gravis
● Pernicious anemia
● Reactive arthritis
● Rheumatoid arthritis
● Sjögren syndrome
● Systemic lupus erythematosus
● Type I diabetes
Symptoms
Symptoms will vary, based on the type and location of the faulty immune response. Common
symptoms include:
● Fatigue
● Fever
● General ill feeling (malaise)
● Joint pain
● Rash
Exams and Tests
The health care provider will do a physical exam. Signs depend on the type of disease.
Tests that may be done to diagnose an autoimmune disorder include:
● Antinuclear antibody tests
● Autoantibody tests
● CBC
● Comprehensive metabolic panel
● C-reactive protein (CRP)
● Erythrocyte sedimentation rate (ESR)
● Urinalysis
Treatment
The goals of treatment are to:
● Reduce symptoms
● Control the autoimmune process
● Maintain the body's ability to fight disease
Treatments will depend on your disease and symptoms. Types of treatments include:
● Supplements to replace a substance that the body lacks, such as thyroid hormone, vitamin B12,
or insulin, due to the autoimmune disease
● Blood transfusions if blood is affected
● Physical therapy to help with movement if the bones, joints, or muscles are affected
Many people take medicines to reduce the immune system's abnormal response. These are often
called immunosuppressive medicines. Examples include corticosteroids (such as prednisone) and
nonsteroid drugs such as azathioprine, cyclophosphamide, mycophenolate, sirolimus, or
tacrolimus. Targeted drugs such as tumor necrosis factor (TNF) blockers and Interleukin
inhibitors can be used for some diseases.
Outlook (Prognosis)
The outcome depends on the disease. Most autoimmune diseases are chronic, but many can be
controlled with treatment.
Symptoms of autoimmune disorders can come and go. When symptoms get worse, it is called a
flare-up.
Possible Complications
Complications depend on the disease. Medicines used to suppress the immune system can cause
severe side effects, such as higher risk of infections.
When to Contact a Medical Professional
Call your provider if you develop symptoms of an autoimmune disorder.
Prevention
There is no known prevention for most autoimmune disorders.
Transplantation:
Transplant, also called graft or organ transplant, in medicine, a section of tissue or a complete organ
that is removed from its original natural site and transferred to a new position in the same person or
in a separate individual. The term, like the synonym graft, was borrowed from horticulture. Both
words imply that success will result in a healthy and flourishing graft or transplant, which will gain its
nourishment from its new environment.
You may need an organ transplant if one of your organs has failed. This can happen because of
illness or injury. When you have an organ transplant, doctors remove an organ from another person
and place it in your body. The organ may come from a living donor or a donor who has died.
● Heart
● Intestine
● Kidney
● Liver
● Lung
● Pancreas
You often have to wait a long time for an organ transplant. Doctors must match donors to recipients
to reduce the risk of transplant rejection. Rejection happens when your immune system attacks the
new organ. If you have a transplant, you must take drugs the rest of your life to help keep your body
from rejecting the new organ.
Unfortunately, doctors and patients now face a new obstacle: The demand for
transplants has far surpassed the supply of donated organs. Simply put, there
aren't enough organ donors, so patients must wait months, even years, for their
chance at recovery.
In this article, we'll look the three major processes involved in organ
transplantation: the organ distribution system, the surgery itself and
the post-surgery recovery. We'll also explore how scientists and politicians are
working to remedy the organ-shortage problem.
Kidneys and livers may be transplanted from a living donor, since people are
born with an extra kidney and the liver is regenerative. Even a lung can be
transplanted from a living donor, but this is still very rare. For these procedures,
a patient will generally find a willing donor in a friend or family member. If the
donor is a match, they can proceed directly to the surgery stage. A smaller
number of living transplants come from charitable people donating for the
general good.
In the United States, a patient who wants an organ transplant from a cadaverous
donor must become part of an elaborate nationwide organ distribution system.
This system, known collectively as the Organ Procurement and
Transplantation Network (OPTN), is operated by the United Network for Organ
Sharing (UNOS), an independent nonprofit organization working under contract
with the U.S. Department of Health and Human Services.
Transplant Rejection
The different types of grafts described above have varying risks for rejection. Rejection
occurs when the recipient’s immune system recognizes the donor tissue as foreign
(non-self), triggering an immune response. The major histocompatibility complex
markers MHC I and MHC II, more specifically identified as human leukocyte antigens
(HLAs), play a role in transplant rejection. The HLAs expressed in tissue transplanted
from a genetically different individual or species may be recognized as non-self
molecules by the host’s dendritic cells. If this occurs, the dendritic cells will process
and present the foreign HLAs to the host’s helper T cells and cytotoxic T cells, thereby
activating them. Cytotoxic T cells then target and kill the grafted cells through the same
mechanism they use to kill virus-infected cells; helper T cells may also release
cytokines that activate macrophages to kill graft cells.
With the three highly polymorphic MHC I genes in humans (HLA-A, HLA-B, and HLA-C)
determining compatibility, each with many alleles segregating in a population, odds are
extremely low that a randomly chosen donor will match a recipient’s six-allele genotype
(the two alleles at each locus are expressed codominantly). This is why a parent or a
sibling may be the best donor in many situations—a genetic match between the MHC
genes is much more likely and the organ is much less likely to be rejected.
Although matching all of the MHC genes can lower the risk for rejection, there are a
number of additional gene products that also play a role in stimulating responses
against grafted tissue. Because of this, no non-self grafted tissue is likely to completely
avoid rejection. However, the more similar the MHC gene match, the more likely the
graft is to be tolerated for a longer time. Most transplant recipients, even those with
tissues well matched to their MHC genes, require treatment with immunosuppressant
drugs for the rest of their lives. This can make them more vulnerable than the general
population to complications from infectious diseases. It can also result in
transplant-related malignancies because the body’s normal defenses
against cancer cells are being suppressed.
Transplants that are from a genetically unrelated donor of the same species are
termed allografts. Allogeneic transplantation is deemed the last resort for the
treatment of chronic organ failure. Even with the aid of organ preservation and the
advances in immunosuppression, the major complication post-transplantation is
rejection. Rejection occurs despite pre-transplant tissue typing/blood analysis and
is seen in almost all transplant recipients, to varying degrees. Outside hyperacute
rejection, which occurs due to the presence of pre-existing antibodies (resulting
from pregnancy, blood transfusions and/or previous transplants), transplant
rejection (Figure 1) can be split broadly into two types; acute and chronic. Acute
rejection is thought to be solely an immunological response, whereas chronic
rejectioninvolves both immunologic and non-immunologic mechanisms.
Drug treatment
Transplant rejection involves the body producing T and B cell and immune responses that
recognise markers on foreign tissue called antigens. Treatment regimens used to prevent
rejection employ drugs from different classes taking advantage of their complementary actions
and minimising toxicity. Drug choice depends on the organ being transplanted and is tailored for
each individual to minimise transplant-related morbidity.
Double drug treatment – usually a calcineurin inhibitor such as Prograf (Tacrolimus) or Neoral
(cyclosporine) with either Imuran (azathioprine) or CellCept (mycophenolate).
Triple drug treatment – usually a calcineurin inhibitor such as Prograf (Tacrolimus) or Neoral
(cyclosporine), a corticosteroid and either Imuran (azathioprine) or CellCept (mycophenolate).
Quadruple drug treatment – as for triple drug treatment plus an induction course with an
immunosuppressant antibody (antithymocyte globulin, basiliximab or daclizumab).
Immunosuppression for organ transplants usually involves triple or quadruple drug treatment.
The intensity of immunosuppression is initially high but tends to be reduced to a maintenance
level that is determined by individual factors and the type of organ transplant. Your specialist
will know which the best therapy is for you.
Initial Treatment
Initially a specialist may give a corticosteroid and either Imuran (azathioprine) or mycophenolate
(sometimes with a calcineurin inhibitors such as Prograf (tacrolimus) or Neoral (cyclosporin))
for initial immunosuppression immediately before cadaveric donor transplantation, or for several
days before planned live donor transplantation.
Calcineurin inhibitors
Calcineurin inhibitors react in the body to block the acitivity of calcineurin. This results in
controlling the body’s immune response and reducing the body recognising and attacking the
foreign organ.
Neoral (cyclosporin) is available as a microemulsion, which has greatly enhanced its oral
bioavailability, with much less variation in absorption within and between patients.
Evidence suggests that Prograf (tacrolimus) may be slightly more efficacious than Neoral
(cyclosporin) and they are now used in equal numbers of patients worldwide. Absorption is
hindered by food, so usually it needs to be taken on an empty stomach.
Sirolimus
Imuran (azathioprine) is used in 60% of patients and mycophenolate mofetil in 40%. These drugs
stop the production of cells called B and T cell that cause the immune response.
Corticosteroids
Corticosteroids are thought to reduce the synthesis and secretion of a variety of inflammatory
mediators.
Alopecia
Dyspepsia
Increased susceptibility to infections (eg oral, vaginal and intertriginous candidiasis)
Masking of signs of infection
Increased appetite
Delayed wound healing
Some of the rare serious side effects that can occur in less than 1% are: